JP4860879B2 - Breath test apparatus and method - Google Patents

Description

【０１４６】
吸収曲線の変化に関して測定された呼気検査結果の関連性を克服するために、本発明の好ましい実施例によれば、呼気検査機器は、種々の補償手順、例えば上述のようなソフト較正、自己較正または患者較正の各手順を組み込んでよい。このような較正手順の１つが実施される場合、例えば同位体比（「陰性」患者）の有意な変化を示さない患者の呼気の試料が較正法において使用され、その呼気の同位体比をＲ_pdbによって概算することができる。吸収曲線のパラメータは、反復較正手順によって調整され、予想通り、測定された比がＲ_pdbの比であることが実際に見出される。真の比が２０δまたはＲ_pdbの値よりも下にあることがたとえ判っていても、このようなＲ_pdbに対する推定近似値を使用することは、測定されたＤｏＢ値に対して小さな影響しか与えない。従って例えば、上述の陰性患者の試料の真の比が、推定Ｒ_pdb＝１．１１２７３％ではなく、実際にはＲ＝１．０７％（陰性患者の典型的な値）である場合、Ｒ_pdb近似値の使用から生じる、測定されたＤｏＢの誤差は、測定値の３％オーダに過ぎない。このことは、５δではなく、５．１５δの読み取りが得られることを意味し、このような偏差は全く重大ではない。測定されたＤｏＢの絶対値の、被検者のベースライン・レベルとの関連性は最小限である。
【０１４７】
異常に高いベースライン比、Ｒ_pdbの推定値を上回る６０δものベースライン比さえも有する被検者の他方の極端な例では、反復較正法を使用することによって、得られたＤｏＢ測定値が受ける影響は１δ未満となる。相異なる被検者間のベースライン同位体比の広がりは、６０δというこの値をかなり下回るのが典型的なので、上述のような本発明の好ましい較正法の利用は、正確な呼気検査結果を得ることを可能にする。このような結果は、一般に受け入れられたＤｏＢパラメータに帰することができ、検査された患者の実際のベースラインとは無関係である。
【０１４８】
上述の較正で用いられたＲ_pdb 近似によって生じたＤｏＢの測定値の偏差が小さいものであっても、この偏差は、好ましくは既知の同位体比を有する試料について比を測定することにより、例えば機器の較正チェックを行うことにより補償することができる。本発明の別の好ましい実施例によれば、δ’の上述の定義は、「同位体比の相対変化(relative Change in the Isotopic Ratio)」またはＲＣＩＲとして知られる別のパラメータで使用される。パラメータＲＣＩＲは、吐き出された呼気の同位体比の増加を見極めるために、従来のＤｏＢの代わりに使用されるのが好ましい。ＲＣＩＲは次の表現によって定義付けされる。
ＲＣＩＲ_n＝ＲＣＩＲ_n-1 ＋ １０００＊（Ｒ_n−Ｒ_n-1）／Ｒ_n-1
この場合Ｒ_nは、測定値ｎに対応する¹³ＣＯ₂／¹²ＣＯ₂同位体比である。定義により、ベースライン測定では、ＲＣＩＲ₀＝０である。
【０１４９】
ＲＣＩＲの上記定義によれば、基準化は、前の測定点Ｒ_n-1に関して実施されるのが好ましい。ＲＣＩＲに対しては別の好ましい定義を使用することもできる：
ＲＣＩＲ_n（＋）＝ＲＣＩＲ_n-1 ＋ １０００＊（Ｒ_n−Ｒ_n-1）／Ｒ_n
この場合基準化は目下の測定点における比に関して行われる。陽性結果Ｒ_n＞Ｒ_n-1を示す呼気検査の経過中、ＲＣＩＲ_n（＋）を使用して達成された結果は、前に定義したＲＣＩＲ_nを使用して得られた結果よりも、Ｒ_pdbに関して得られた結果に近似する。
【０１５０】
本発明の別の好ましい実施例によれば、ＲＣＩＲに関するこれら２つのタイプの基準化は、測定された同位体比が増加しているかまたは減少しているかに応じて、それぞれの測定の結果を算出するのに交互に用いられる。同位体比が上昇している場合、つまりＲ_n-1＜Ｒ_nの場合、第２の定義ＲＣＩＲ（＋）が用いられる。同位体比が降下している場合、つまりＲ_n＜Ｒ_n-1の場合、第１の定義ＲＣＩＲ_nが用いられる。交互のＲＣＩＲパラメータを用いるこの算出法は、比曲線が増加から減少へ、またはその逆に向きを変えるとき、またはそれが機器的な源から発するものであれ生理学的な源から発するものであれ、測定点に高レベルのノイズがあるときに、結果の傾きを平滑化するのに有利である。この方法はまた、プロットされた曲線の全体的な傾向から特に逸脱した測定点を補償するのにも有利である。
【０１５１】
測定された同位体比の傾向に従って交互に定義付けされるＲＣＩＲパラメータを使用することの更なる利点は、得られた結果の精度にある。単一の定義としてのＲＣＩＲパラメータを使用すると、変化の向きに応じて、比の変化が亢進されるか、または比の変化に重きが置かれなくなる。従って例えば、前の読み取り値であるＲ_n-1に対して基準化された第１のＲＣＩＲ_nパラメータを使用すると、増加する比が誇張される。それというのも増大中、ＲＣＩＲの分母のＲ_n-1はＲ_nよりも小さいからである。同様に、ＲＣＩＲ_nを使用すると、降下する比の減少率が明らかに小さくなる。それというのも分母Ｒ_n-1が現在の比Ｒ_nよりも大きいからである。ＲＣＩＲ_n（＋）パラメータを使用すると、逆の影響が現れ、増大に対しては重きが置かれず、減少は誇張されるようになる。
【０１５２】
その結果、実施される呼気検査の分析に、ＲＣＩＲパラメータのうちの一方または他方が使用される場合、波状の比曲線は比の誤差が蓄積されたものとなる。これに対して、測定値の傾向に応じて交互のＲＣＩＲパラメータを使用する本発明の好ましい実施例によれば、波状の曲線は真の測定結果を常に反映し、その結果例えば、比がその元の値に戻ると、曲線も常に元のレベルに戻る。
【０１５３】
測定経過中に生じる機器のドリフトは、従来のＤｏＢに対して与える影響とは著しく異なり、パラメータＲＣＩＲには影響を与えない。上述の表１の最後の列には、与えられた同位体の値毎に算出されたＲＣＩＲパラメータの値が示されている。ここから明らかなように、ＲＣＩＲ値は高ＤｏＢ値で小さな偏差を伴いながら、古典的なＤｏＢの値に追従する。
【０１５４】
本発明の別の好ましい実施例によれば、ＲＣＩＲは、例えば１時間をはるかに超える上述の検査のように、比較的長時間にわたって呼気検査を実施する際の主要な問題を大幅に克服する測定法に用いることができる。このような状況では、例えば環境条件の変化、具体的には温度変化に伴って吸収曲線に変化が生じることにより、機器にはドラフトが多く発生する。この状況において、検査開始近くでベースライン基準が取られた場合、このベースライン測定値と、検査中かなり後で得られた同位体比とを正確に比較する簡単な方法はない。それというのは一般に測定条件が変化したおそれがあるからである。従ってその比較は妥当なものではない。
【０１５５】
さらに、呼気検査で用いられるいくつかを含む、光学分光気体分析法の場合、試料を、ベースライン試料と同一の主要同位体成分濃度にする必要があるので、試料セル内で測定された光透過率（吸収率）を、試料セル内の成分気体の濃度に直接的に関連付けすることが可能である。捕集された各試料を不活性ガスによって予め決められた濃度に希薄化することにより、濃度を等しくすることができる。濃度は、検査されるべき通常の達成濃度の範囲の下限であるように選択されるのが典型的なので、実際に捕集された試料の大部分を、予め決められた同一濃度値に希薄化することができる。
【０１５６】
Otsuka Pharmaceutical Co.によりＰＣＴ出願された上述の国際公開第97/14029号（WO97/14029）パンフレットには、２つの試料間の濃度を等しくするために、２つの試料バッグの濃度を比較し、濃度の高い方の試料を低い方の濃度に希薄化する方法が記載されている。残念ながら、それぞれが異なる試料バッグに捕集された多数の試料に対して、または本発明において説明するように試料の呼気を効率的に準連続的にモニターするオンライン測定法に対して、最低濃度に希薄化する方法を適用するのは現実的でない。大規模な試料集合を比較するには、試料を取り扱い、一次的に保存する複雑なシステムが必要となる。それというのも、各試料は他のどの試料とも最終的に比較される必要があるからである。
【０１５７】
さらに、典型的な呼気検査の継続中には安定した測定条件を一般には維持することができない以上、Otsukaの方法の場合、試料の同位体比の変化に関連する比Ｒ₀が使用され、この比Ｒ₀は測定された試料の比から隔たっている場合があるので、別の不都合が生じる。同様に、ｎ番目の試料をｎ−１番目の試料と比較する場合、比Ｒ_n-1が基準化に使用されるとしたら、その結果の傾向は極度に誇張され、いかなる変化も過度に強調される。
【０１５８】
本発明において説明した好ましい実施例に従って、交互のＰＣＩＲパラメータを利用することにより、個々の試料対ｎ−１およびｎを同一濃度にすることを可能にするOtsukaの方法における上述の不都合が、他の試料対を参照することなしに解決される。その後で、ｎ番目の試料の新しい測定値に関連してｎ＋１番目の試料が測定される。
【０１５９】
従来の二酸化炭素呼気検査に共通に用いられる、試料の正しい希薄化を達成する別の方法は、¹²ＣＯ₂ＩＲ透過率を既知の濃度の基準試料と比較することにより行われる。上述の理由から、比較吸収測定は大幅に異なる時点に行われる場合には不正確になるおそれがあるので、試料を等しい濃度にする能力は、吸収測定自体に影響を与える機器安定性の同じ問題によっても影響を受ける。従ってこれに関して用いられる方法によれば、かなり異なる時点に試料が捕集され測定されているときには、呼気検査の精度は、ベースライン試料を参照して正確な比較吸収測定を実施するための能力に、２つの別個の形で関連する。つまり第１は、試料を同一濃度に正確に希薄化する能力であり、第２は、実際の吸収測定を正確に実施する能力である。
【０１６０】
このような問題を克服する数多くの方法がある。１つの方法は、極めて多量なベースライン試料を捕集し、これを個別の部分に分けることである。これらの個別の部分は、検査が進行するのに従って捕集されたそれぞれ後続の試料を、この後続の試料が測定されるときの条件下で、元のベースライン試料の一部と比較するのに充分に足るものとなる。これによりその比較はより正確になる。あるいは、ベースライン試料の別個の試料は、連続する呼気の比較毎に抜き出されてもよい。それぞれの比較測定のために分割した後で充分となる大規模な初期ベースライン試料を捕集するという実際的な問題により、これらの方法は実施するのに厄介であり、一般に容易には実現できない。
【０１６１】
R.Grisar他に発行された米国特許第5,146,294号明細書で提案された別のよりシンプルな手順においては、基準気体から成る連続的な試料を供給するための保存コンテナを使用する。基準気体は、希薄化された呼気試料の各測定間に、希薄化された試料呼気の条件と出来る限り同一の条件下で、測定チャンバ内に移される。このような方法の精度は、システムを温度安定化できる精度と、基準試料を同一圧力条件下で繰返し測定できる精度とによって限定されるように思われる。
【０１６２】
本発明の別の好ましい実施例によれば、上記のものとは異なる基準測定法において、吐き出された呼気から成る単独の初期ベースライン試料を捕集し、検査中に捕集されたそれぞれの試料の各測定間に測定セルに、または測定セルからベースライン試料を搬入・搬出することにより、検査中に捕集されたそれぞれの試料の測定直前および／または測定直後に同じベースライン試料を繰返し測定する。こうしてベースライン試料は、捕集された試料の条件と同様の条件下で測定される。この方法を実施するには、ロスや漏れや希薄化によって単独のベースライン試料が汚染されるのを回避するために、正確な気体取り扱いシステムが必要となる。
【０１６３】
あるいはかつ好ましくは、またよりシンプルに、このような単独ベースライン試料は固有の基準セル内に保存され、新たに捕集された試料の測定毎に、測定セル内の試料気体と比較されてもよい。このような手段はそれぞれの測定を実施するために、相異なるセル相互間で測定路を切り換えなければならないという欠点を有する。
【０１６４】
上述の手順の全てを実施するための較正法は、絶対固定比または可変比に対して基準化された固定点からの同位体比の変化に対する種々異なる定義を用いて確立されることが好ましい。この場合測定比の同位体偏差は、どの基準比が用いられたかに応じて、以下のいずれの表現によっても与えられる。
（ａ） （Ｒ_n−Ｒ_0(n)）＊１０００／Ｒ_0(n) または
（ｂ） （Ｒ_n−Ｒ_0(n)）＊１０００／Ｒ_pdb
この場合Ｒ_nおよびＲ_0(n)は、それぞれｎ番目の測定点で測定された測定同位体比およびベースライン基準である。
【０１６５】
例えば過剰の機器ドリフトにより、Ｒ_pdbに対して行われるような絶対基準化測定を達成できない場合、相対同位体偏差は次の形を取ってよい：
（ｃ） （Ｒ_n−Ｒ_0(n)）＊１０００／Ｒ_n
Ｒ_n≧Ｒ_0(n)なので、表現（ｃ）は（ａ）よりも、標準的なＰＤＢに関連する表現（ｂ）に近似している。
【０１６６】
基準比がベースライン測定値ではない場合には、この点からの同位体比の変化は、前の結果に関して算出されることが望ましい。従って、用いられる定義に応じて、前の結果に関して以下の項のうちの一方を差し引くことにより、偏差が得られる：
（ｄ） （Ｒ_n−Ｒ_ref(n)）＊１０００／Ｒ_ref(n) または
（ｅ） （Ｒ_n−Ｒ_ref(n)）＊１０００／Ｒ_pdb
この場合、Ｒ_nおよびＲ_ref(n)は、それぞれｎ番目の測定点で測定された測定比自体および基準比である。
【０１６７】
例えば過剰の機器ドリフトにより、Ｒ_pdbに対して行われるような絶対基準化測定を達成できない場合、相対同位体偏差は次の形を取ることが好ましい：
（ｆ） （Ｒ_n−Ｒ_ref(n)）＊１０００／Ｒ_n
Ｒ_n≧Ｒ_0(n)なので、表現（ｆ）は（ｄ）よりも、標準的なＰＤＢに関連する表現（ｅ）に近似している。
【０１６８】
第１の点（ベースライン）に関して、同位体比の相対変化は次のように表現することができる：
（Ｒ₀−Ｒ_ref(0)）＊１０００／Ｒ_{ref(0),pdb または 0}
これに対してｎ番目の測定点に関しては、測定がベースラインに関して実施される場合には、：
（R_n-R_ref(n))*1000/R_{ref(n),pdb または n} - （R₀-R_ref(0))*1000/R_{ref(0),pdb または 0}
または、ＲＣＩＲ算出法が用いられる場合には、
（R_n-R_ref(n))*1000/R_{ref(n),pdb または n} - （R_n-1-R_ref(n-1))*1000/R_{ref(n-1),pdb または n-1}
【０１６９】
本発明の別の好ましい実施例によれば、ＲＣＩＲパラメータを使用する方法が提案される。ＲＣＩＲパラメータは、長時間にわたる呼気検査に際して、捕集された試料を単独のベースライン試料と比較することに関する上述の問題を幅広く克服する。この好ましい方法によれば、第１の測定点を除く測定点毎に、試料対が捕集される。第１の測定点では、捕集するのに必要な試料は１つだけであり、これは一般にベースライン試料となる。どの連続的な測定点ｎにおいても、捕集された試料対のうちの一方の試料が、測定点（ｎ−１）、一般的には比較的短時間だけ前の測定点からの試料対のうちの一方の試料と比較されるのに対し、試料対のうちの他方の試料は、次の測定点（ｎ＋１）で捕集されるべき試料対のうちの一方の試料と比較するために保存される。最後の測定点では２つの試料が捕集されるが、しかし一方だけが測定に必要である。それというのも検査はこの点で終了するからである。
【０１７０】
この実施例の方法を、各測定点で２つの別個の試料を「捕集する」という用語で説明したが、しかし実際には、２つの別個の試料を物理的に捕集する必要はない。例えば、単独の試料を捕集し、関連する２つの測定点のそれぞれで半分ずつ使用するか、または、単独の試料を捕集し、これをそれぞれの測定点で一度ずつ、合計二度測定することが可能であり、またはこの方法の他の適切な変更形も考えられる。
【０１７１】
各測定点間の時間は、完全な呼気検査の経過総時間と比べると比較的短く、実施されている検査のタイプに応じて、１分よりもかなり短い時間から３０分を超える時間までの範囲を占めるのが典型的である。従って、１つの測定点と次の測定点との間の比較的短い時間にわたって試料の完全性と測定条件の安定性とをより維持することは、呼気検査の開始から終了までこれを維持するのに比べて簡単である。
【０１７２】
このように、基準の可動枠が生成され、これにより最も近似して生じ得る測定条件下で、前回の測定点との比較が行われ、測定条件が機器のドリフトにより一時的にどのように変化したかとは無関係に、それぞれの測定点を前回の測定点に戻って照会することができる。
【０１７３】
本発明の好ましい実施例による、試料対を比較するコンピュータ上の手順は、図５を参照することにより理解できる。図５は、吸収曲線の変化から生じるような機器のドリフトにより、測定された同位体比Ｒが経過時間の関数として変化し得ることを示している。図示のグラフは一例を挙げるために示したに過ぎない。このプロットは、あたかも呼気検査が真の同位体比に少しの変化もない陰性結果を与えているかのような理想的な固定比に対して、機器によって実際に測定された比の変化を示している。比が実際に変化しているときにより起こりそうな状況に関しても、同様の説明が可能であるが、簡略化するために固定比を使ってこの実施例を説明する
【０１７４】
同位体比の変化を時点ｔ₀におけるベースライン基準測定値と比較する従来の方法を使用すると、時点ｔ₁で測定された同位体比の変化はΔＲ₁となる。時点ｔ₂に設けられた次の測定点では、測定される同位体比の変化は、機器のドリフトの結果として、ΔＲ₂と測定されることになる。ベースライン・レベルからの蓄積された変化はΔＲ₁＋ΔＲ₂となる。同様に第３の測定点ｔ₃では、前回の点からの比の測定された変化はΔＲ₃であり、ベースライン・レベルからの蓄積された変化はΔＲ₁＋ΔＲ₂＋ΔＲ₃となる。グラフから判るように、特に機器の安定性レベルと比較してかなりの時間にわたって持続する呼気検査にとって、種々の値のΔＲ_nは重大である場合があり、蓄積されたΔＲではなおさらである。
【０１７５】
本発明の好ましい実施例によれば、測定点毎に試料対を捕集することにより、このような誤差を実質的に低減することができる。例えば時点ｔ₁においては、捕集された試料対のうちの一方の試料が、時点ｔ₀で測定されたベースライン基準試料と比較するのに用いられる。試料対の第２の試料は、時点ｔ₂まで何もせずに保存され、次いで、時点ｔ₂で捕集された試料対のうちの一方の試料に対する基準試料として使用される。こうして、機器のドリフトによる、測定比ΔＲ₂の変化は無効にされる。それというのも、時点ｔ₁からの試料は時点ｔ₂からの試料と、機器内で本質的に同一の、つまり時点ｔ₂において機器内に現存する条件下で比較されるからである。同様に、時点ｔ₂から保存された第２の試料を時点ｔ₃からの試料と比較することにより、比ΔＲ₃の明らかなシフトを無効にするのが可能になる。同様の議論が、呼気検査の全ての連続的な測定点に当てはまる。
【０１７６】
上述の説明は、各試料の比の測定には極めて短い時間しかかからず、両試料が各時点で同時に測定されることを想定するという点で若干簡略化されている。実際は、それぞれの比の測定には時間Δｔがかかり、例えば点２では、時点ｔ₁から保存された基準試料の比の測定が、時点ｔ₂で捕集された試料対の一方を測定するよりも早く、時間Δｔで行われる。この時間Δｔの経過中、機器のドリフトは持続し、その結果時点ｔ₂で測定された比ｒ₂は、時点（ｔ₂＋Δｔ）で測定された比とは、量Δｒだけ異なる。しかし、比の測定にかかる時間Δｔが、連続的な測定点の間の経過時間よりも一般には著しく短いので、本発明のこの好ましい実施例による試料対測定法を利用すると、かなり精度が増大し、機器のドリフトからの免疫性も増大する。
【０１７７】
さらに、本発明のこの好ましい実施例による試料対法は、各試料を目標濃度に希薄化し、達成された濃度を測定するのにかかる時間を考慮しても、なおも測定を有意義に改善する。このようなプロセスは同一濃度で試料が比較されるように実施される。希薄化および濃度測定のプロセスは実際には、比測定自体を実施するのにかかる時間Δｔよりもかなり長くかかる。前回の測定点から捕集された基準試料と、目下測定されている試料との双方に関して、希薄化および濃度測定の手順が、測定点相互間の最小限の時間で実施されるならば、比の測定を行う時点に達したときには、試料は既に目標濃度に希薄化されており、すぐに測定される準備が整っている。しかも比較測定間の時間差はΔｔ未満である。
【０１７８】
試料対を捕集して測定し、試料の同位体比の相対変化を算出するためのＲＣＩＲパラメータを使用するこの好ましい方法は有利であり、また全てのタイプの呼気検査に適用可能である。このような呼気検査のタイプは、試料捕集のためにバッグを使用し、次いで試料の捕集時点および捕集場所とは必ずしも関係しない時点および場所で分析される呼気検査と、被検者が呼気検査機器に接続されて、これによりその呼気を呼気検査機器によりほとんど連続的にモニター可能な状態で、リアルタイムに行われる呼気検査との双方を含む。
【０１７９】
（ｃ） ベースライン見極め法
公知の技術の場合、標識基質の摂取前に得られた単独の呼気試料または試料群から取られた単独の測定値の同位体比を検出することにより、ベースラインが見極められる。機器のドリフトまたは高ノイズレベルにより、または、臨床的な理由から連続的な呼気が著しく異なる同位体比を与えるときに、患者によって供給される呼気中の生理学的「ノイズ」により、得られた単独のベースライン点が正しくない場合に、上記方法は不正確な結果を生み出す場合がある。
【０１８０】
潜在的な不正確さのこのような源を克服するために、本発明の別の好ましい実施例によれば、ベースライン見極め法の働きにより、測定されたベースライン点の質を再検討し、必要ならば、標識基質を患者が摂取する前に、１つまたは複数の付加的なベースライン点を測定する。
【０１８１】
ベースライン測定に関連した第１の付加的な好ましい実施例によれば、機器内で作業可能な自己診断手順が、例えば第１のベースライン測定点を形成する別個の結果のばらつきが低標準偏差で存在することによって、または目標値に近似する二酸化炭素濃度が達成されることによって見極められるように、測定された点の質が高いことを示す場合には、制御システムは、単独のベースライン測定が充分に正確であるという結論を下す。
【０１８２】
別の好ましい実施例によれば、第２のベースライン測定値が取られる。２つの測定値が互いの予め決められた値内にある場合、機器的にも生理学的にも、ベースライン測定値には何の妨害も働いていないと推定され、２つの値の単純平均が用いられるのが好ましい。これに対して２つの値の間に食い違いが検出されるか、または、例えば上述の基準により見極められるように、これらの点の１つが低質であると疑われる場合には、多くの可能性が現れる。低質の点は廃棄されて、良好な点だけがベースライン・レベルを定義付けすることが好ましい。あるいはかつ好ましくは、システムは第３のベースライン点の測定を要求することもできる。この第３のベースライン点の結果により、測定結果のうちのどれを使用するかを見極めることが好ましい。第１の２つの値がノイズ問題によりばらついていると思われる場合には、この方法では３つの値全ての単純平均が取られる。あるいは、第１の２つの値のうちの一方が他の２つとは大幅に食い違うことが、第３の測定値から明らかな場合には、第１の２つの値の一方は、不良値として拒絶することができる。
【０１８３】
本発明の別の好ましい実施例によれば、ベースライン測定は、検査の進行をスピードアップするように行われる。従って例えば第２の点は、第１の点の分析完了前に捕集されることが好ましい。第１の点が低質であり使用できないことが、第２の点の測定完了前に明らかになる場合、第２の点の測定完了前に、計算ルーティンは第３のベースライン試料の捕集を要求する。
【０１８４】
本発明の別の好ましい実施例によれば、検査をよりスピードアップするために、第２の測定値の結果を知る前に、ただし第２のベースライン測定のための呼気試料を捕集した後で、摂取するための標識基質を患者に与える。この場合、例えば測定値を形成する別個の点の標準偏差により、または達成されたＣＯ₂目標濃度の精度により見極められるように、測定値の質をチェックした結果、測定値のうちの一方が正確でないことが明らかになった場合、ベースラインを計算する上でその測定値を廃棄することができる。両測定値の質が良好な場合には、これらの値の平均が用いられてよい。
【０１８５】
（ｄ） 閾値利用法
特異的な臨床状態を検出するための呼気検査は、多くの他の診断検査と同じように、特定の結果または検査の陽性結果を示すようなレベルの達成に依存する。求められている臨床状態が存在しないことに関して決定的な診断を提供すること、換言すれば陰性結果を定義付けすることは、一層難しい作業である。
【０１８６】
呼気検査の作業機能は、被検者の呼気試料成分の同位体比に生じた変化が、求められている作用に関連して臨床的に有意になると、それを見極めることである。従来技術の多くに用いられているようなこの見極めの基準は、検査に割り当てられた時間に、またはその時間内にＤｏＢが所定の閾値レベルを超えたか否かである。結果が陽性の場合、ＤｏＢ値の緩やかな上方へのドリフトが得られたときのように、閾値との交差が確固たるものではないときに若干の疑わしさがまだ残るとしても、判断はよりシンプルである。しかし、ＤｏＢがベースラインと閾値との間をさまよい、しかも時折、おそらくはランダム・ノイズによりこのＤｏＢが閾値を超えて動かされる場合、結果が本当に陰性であるという確固たる診断を下すのは一層難しい作業である。人口に対するかなりの比率で潰瘍が広範囲に蔓延しており、上部消化管が同様の関連状態を有しているので、陰性結果の解釈は、上部消化管のＨ．ピロリの存在を検出するために一般に用いられる尿素呼気検査においては特に重要である。
【０１８７】
この問題の１つの解決手段は、テストがより長時間にわたって持続することを可能にし、これにより結果が陰性のままであるか否かを見極めることである。しかしこのことは、患者に不便をかけ、また別の患者を検査するのに使用できるはずの高価な機器を不要に占有することになる。従って、明確な結果、特に陰性結果を最小限の時間で得るのを可能にする最適な呼気検査閾値レベルを定義する手段を講じることが重要である。
【０１８８】
このような目的を達成するために、また可能な限り最短の測定時間で最高の感度および特定性を達成するために、本発明の別の好ましい実施例による呼気検査分析器は、患者の呼気の同位体比の変化が臨床的に有意か否かを見極めるために固定的な基準を利用しない。その代わりに基準は、検査中に作用する多くのファクタに従って検査の経過中に変化させられる。このファクタには、例えば検査の経過時間、検査を実施する機器のノイズレベル、および検査の生理学的結果が含まれる。
【０１８９】
さらに、同位体比の変化の伝統的に用いられる測定値は、ベースライン・レベルに関する比のレベルであったが、本発明の別の好ましい実施例によれば、測定値は、ベースライン・レベルではなく前回の測定点に関する変化、または同位体レベルの変化率、または、変化の経過をプロットするのに用いることのできる別の性質であってよい。
【０１９０】
これらの新規の測定法を示すためにここに提示する本発明の好ましい実施例の場合、その検査の完了を判断するために、充分なデータが蓄積されたか否かを見極めるように、閾値利用法がリアルタイムの検査結果を用いる。このような見極めは、動的閾値レベルを用いることにより達成される。このレベルの値は、測定経過中に閾値利用法によって、以下の量のうちの１つまたは複数の量の関数として変化させることができる：
（ｉ） 蓄積されたデータの性質、すなわち検査が良好に定義付けされた結果を与えているか否かの関数、
(ii) 得られた結果のレベルおよび傾向の関数、
(iii) 蓄積データの標準偏差の関数、および、
(iv) その特定の時点で用いられている特定の機器のノイズおよびドリフトのレベルの関数。
【０１９１】
さらに別の好ましい実施例によれば、２つの閾値、つまり上側および下側の閾値を利用することができる。これらの閾値は、捕集されたデータの有意性が明らかになるにつれて収束する。
【０１９２】
可変閾値の使用を見極める方法は、口腔活性の沈静化後の検査開始時と、検査進行中との間で区別することができる。大量のデータを蓄積する前の検査早期には、決定的な結果を判断するために、点は陽性結果を示唆する、ベースラインの明らかに上方にあるか、または、陰性結果を示唆する、ベースラインに極めて密接した位置になければならない。検査が進行し、大量の蓄積された測定点の生理学的結果が考慮に入れられるのに従って、使用されるべき閾値基準はより統計学的に、蓄積されたデータに基づくようになるべきである。
【０１９３】
これら２つのアプローチの結果を図６に示す。図６は、二重の動的な閾値基準を使用する好ましい方法を示している。図６には、時点ｔ₀における同位体標識基質の摂取から経過した時間の関数として使用された閾値のプロットが示されている。時点ｔ₀における検査開始から時点ｔ₁までの領域５００では、上側閾値に達したか否かを見極める上で、呼気試料は一般には考慮に入れられない。なぜならば、患者の口内に存在する細菌によって基質が衰弱することにより口腔活性が存在しているかもしれないからである。これに対して有意な口腔活性が存在していないと口腔活性検出システムが検出した場合には、上側閾値と交差していると見極める上で、例え時点ｔ₀からのものであっても、上昇する結果を考慮に入れることができる。ベースラインに近接する結果は一般的には常に考慮に入れることができる。それというのもこのような結果は、口腔活性が存在するとしても、その存在によっては影響されないことが明らかだからである。
【０１９４】
時間ｔ₁の経過後、口腔活性が存在する場合にはこの活性が沈静化し、捕集された呼気の全てが検査結果の計算のために考慮に入れられると、２つの閾値、つまり上側閾値Ｔ_u５０６と、下側閾値Ｔ_l５０８とが使用される。領域５０２全体を通して、蓄積されているデータが極めて僅かしかない場合には、Ｔ_uおよびＴ_lの大幅に異なる値８δおよび２δが図６の好ましい実施例において使用される。下側の結果２δは陰性結果と見なされ、これに対して上側の結果８δは陽性結果と見なされる。Ｔ_uとＴ_lとの間の領域内に存在する結果は、不明確であり、より多くのデータの蓄積を必要とする。別の好ましい実施例によれば、閾値レベルはこの領域において一定である必要はなく、時点ｔ₁で大きく離れた場所で始まり、時間とともにゆっくりと収束する。これは別の上側閾値曲線５０７によって示した通りである。
【０１９５】
この好ましい実施例の重要な観点は、尿素の投与後たった４分であることも可能な時間ｔ₁に達するまでに、得られた結果が所期のベースライン、つまり記載の好ましい実施例の場合８δおよび２δから充分に逸脱している場合、陽性または陰性の明確な診断を下すことが既に可能なことである。明確な診断のための好ましい基準は、下側閾値を下回るいずれの点も除外して、上側閾値の上方に２つの点が得られた場合、診断は陽性である、ということである。同様に、上側閾値を上回るいずれの点も除外して、下側閾値の下方に２つの点が存在した場合、これは陰性診断を提供するのに充分な基準となる。結果が本当に陰性なのかどうかを見極める上での上述のような難しさを心に留めた、陰性診断のためのより厳格で好ましい基準は、尿素投与後の３つまたは４つの連続する点の存在である。これらの点は下側閾値よりも下方にあるか、または平均してこの閾値よりも下方にあり、１δ未満の標準偏差と、１分当たり０．１δ未満の勾配とを有し、機器の有意なドリフトまたは傾きを有さない。質的に云えば、このことは、ほとんど平らであるべきＤｏＢプロットを示す測定に際して、履歴上安定的に動作することが知られている機器において、いかなる従来の方法よりも早く陰性結果を見極め可能であることを示唆している。従って、診断を提供できる速度に関して、本発明の呼気検査の好ましい実施例の１つの観点は、陽性結果についても陰性結果についても、従来の機器および方法の実施例とは大きな違いを示す。
【０１９６】
図６の実施例の場合には６分で示される時間ｔ₂の経過後、充分に多くの点が蓄積されている場合には、結果の標準偏差は降下するはずであり、検査の生理学的結果は、いずれかの方向で決定的ならば充分に明白なはずなので、閾値を互いに徐々に接近させ、進行中の検査に最高の感度と特定性とを提供する方向に動かすことができる。閾値同士の閉鎖を開始する時点ｔ₂と、閾値５１０，５１２の閉鎖自体の速度と、両閾値に共通のあらゆるレベルの変化速度とは、データ自体によって決定されるか、または予め決められる。点が最適合曲線から急速に収束する標準偏差を有していると、その結果、閾値はスピーディに閉鎖され動かされることになる。標準偏差がゆっくり収束する場合にはその逆となる。やはり点のばらつき度によって決定される時間ｔ₃後には、２つの閾値は収束して、伝統的に使用されるレベル、この実施例では５δで、１つの閾値５１４となる。この時点からは、この閾値の上方または下方に位置する結果に基づいて診断が行われる。
【０１９７】
これに対して、データ点にばらつきが残っていて、それらの平均レベルが５δに近接している場合には、エラー・メッセージが表示され、有意な結果なしで検査が終結される。
【０１９８】
使用中、図６に示した閾値利用法は次のように作用することが好ましい。６分後に８δを上回らない上昇ＤｏＢ結果を有する被検者は、８分後、７δの閾値で再び評価され、この閾値を上回らない場合には、１０分後、６δの閾値で評価され、伝統的に使用される５δに達するまでこのような評価が行われる。同様に、６分後に２δを下回らない、見極められないＤｏＢ傾向を示す被検者は、８分後、３δの閾値で再び評価され、この閾値を下回らない場合には、１０分後、４δの閾値で評価され、伝統的に使用される５δに達するまでこのような評価が行われる。
【０１９９】
検査の時間が進み、蓄積されたデータが呼気検査メカニズムの生理学的な実態を反映し、これにより陽性の被検者のＤｏＢが時間の進行と共に上昇するにつれて、使用された閾値１５１は、テスト時間の継続と共にゆっくりと上昇することが可能になる。
【０２００】
別の好ましい実施例によれば、下側閾値は、上側閾値と合体して単独の閾値レベルを形成する代わりに、独立して存在し続ける。このことは図６において別の好ましい下側閾値５１６によって示されている。この下側閾値５１６は、例示においては４δに示されている或る程度上方のレベルで一定のままであるか、または陰性結果と陽性結果との区別がより明らかになるにつれて、時間と共にゆっくりと降下する。
【０２０１】
上述の好ましい実施例に従って可変の閾値を使用することの有効性は、このような閾値の実施例を組み込んだ呼気テスターで得られた結果を、標準モニター検査法によって得られた結果と比較することによって検証された。Ｈ．ピロリ呼気検査の場合、このような標準モニター法は、患者の胃からの生検材料の内視鏡的な捕集によって、次いで組織の組織学的検査、または存在する細菌の培養によって行われる。
【０２０２】
本発明の別の好ましい実施例によれば、使用される閾値は、システムの自己診断出力に関連させられる。高いノイズレベルまたは系統的ノイズ・パターン、または結果における傾きを有するような粗悪な結果を与える機器の場合、閾値利用法は、広範囲な初期閾値、つまり比較的高い上側閾値と低い下側閾値とを利用する。低ノイズレベルまたは低レベルのドリフトを有する良好な結果を与える機器の場合、上側および下側の閾値レベルおよびこれらの閾値レベル間の差を全て低下させることができ、陰性結果を定義付けするのに必要な閾値を下回る点の数を次いで減少させることができる。このようにすると、固定された閾値によるよりも早く、検査結果を陰性または陽性と定義付けすることが可能になる。
【０２０３】
本発明の別の好ましい実施例によれば、測定された点の集合が明確な検査結果を与えると考えられるか否かを見極めるのに、閾値利用法が使用される。１つの検査で得られた点のプロットに関数的に近似するように、好ましくは二次の最適合多項式が構成される。この多項式の構成には、口腔活性の効果的な停止に続いて測定されたそれらの点だけが使用される。算出された多項式曲線からのこれらの点の重み付け標準偏差が次いで算出される。重み付けは、ベースラインよりも上方の例えば５δ未満の点に関しては、多項式曲線からの偏差がそのまま採られるように行われる。ベースラインよりも上方の、５δを上回る点に関しては、このような測定値に対するランダム・ノイズの影響ははるかに少なくなるので、計算法は、重み付け標準偏差を算出する目的で有効誤差値として、多項式から点の偏差のうちの２０％だけを採る。このような重み付け標準偏差が１．５σよりも大きいならば、その測定値は、結果のばらつきが大きいので、問題があるとみなされる。
【０２０４】
標準偏差基準に加えて、測定値を決定的でないとして拒絶する際の他の好ましい基準がある。このような好ましい基準の一例を挙げると、この基準は、測定された５つの点のうち少なくとも２つの点が閾値限界内、例えばベースラインより上方の３δ〜７δにある一方、これと同時に、最後に測定された点が、強陽性結果がないことを示す、ベースラインより上方の１０δ未満である場合に用いられる。最後の点だけが陽性結果を示すように思われても、計算ルーティンはその時点で現存するものとして、その測定値を拒絶する。なぜならば、前述の「５つのうち２つ」基準によって不確実性をまねくからである。
【０２０５】
本明細書のいくつかの部分で、上部消化管内のヘリコバクター・ピロリを検出するための尿素呼気検査に関して、手順および計算法を説明してきたが、もちろんこの検査は、呼気検査により実施可能な多くの診断検査の一例にすぎず、本発明はＨ．ピロリ検出呼気検査からもたらされる、好ましい説明例に限定されるものではない。
【０２０６】
具体的に個々まで図示し説明してきたものによって本発明が限定されるものではないことは、当業者には明らかである。むしろ本発明の範囲は、上述の種々の構成要件の組み合わせおよび副次的な組み合わせ、ならびに、これらの構成要件の変更および修正を含むものである。このような組み合わせ、変更および修正は、上記説明を読めば当業者には容易に考えられることであり、しかも従来技術にはないものである。
【図面の簡単な説明】
【図１】 図１は、呼気試料を蓄積して取り扱うための中間チャンバ・システムを組み込んだ、ＰＣＴ国際公開第99/14576号（WO99/14576）パンフレットに開示された呼気テスターの構成部分を示す概略的なブロック・ダイヤグラムである。
【図２】 図２は、図１の呼気テスターに使用されたタイプの、ＮＤＩＲ分子相関分光計を示す斜視図である。
【図３】 図３は、呼気テスターを操作する較正手順の好ましい実施例の主なステップを示すフロー・ダイヤグラムである。
【図４】 図４Ａ〜図４Ｅは、種々の典型的な呼気検査結果、すなわち、本発明の好ましい実施例による事実上連続的にサンプリングおよび分析を行う方法を用いれば正確に解釈可能であるが、しかし、試料呼気の個別のバッグを収集して分析する従来の方法を用いた場合には誤解釈されるおそれのある種々の典型的な呼気検査結果のプロットを示す図である。
【図５】 図５は、連続的に捕集された試料対を、基準試料のベースラインと比較するのではなく、互いに比較する方法の利用を示すグラフである。
【図６】 図６は、同位体比の変化が決定的な結果を提供したと考えられたときにこれを見極めるのに用いられる閾値を、同位体標識基質の摂取からの経過時間の関数として示すグラフである。[0001]
Field of Invention
The present invention relates to the field of breath testing equipment and the use of this equipment, and more particularly to the accuracy, reliability and speed of providing breath testing.
[0002]
Background of the Invention
Gas analyzers are used for many measurement and monitoring functions in science, industry and medicine. Specifically, gas spectrometers are widely used in diagnostic instruments based on the use of breath tests to detect numerous medical conditions in patients. A description of many breath test methodologies and equipment is provided by D. Katzman and E. Carlebach, part of the inventor in this application, WO 99/12471 (WO99 / 12471), titled “Breath Tests”. "Breath Test Analyzer". Ben-Oren, L. Coleman, E. Carlebach, B. Giron and G., part of which is the inventor of the present application, is a method for constructing and operating a gas analyzer such as used in breath test equipment. It is disclosed in the pamphlet of International Publication No. 99/14576 by Levitsky, titled “Isotopic Gas Analyzer”. The application of several breath tests to detect specific medical conditions is included in a patent issued to one of the inventors of the present application. These patents include: U.S. Pat.No. 5,962,335 issued to D. Katzman, titled `` Breath Test for Detection of Drug Metabolism '', and D. Katzman. Issued U.S. Pat.No. 5,944,670, titled `` Breath Test for Detection of Bacterial Infection '', and U.S. Pat. The title is “Breath Test for Detection of Bacterial Infection”. The entire above specification is incorporated herein by reference.
[0003]
Such breath tests are based on ingestion of marker substrates. The marker substrate is cleaved by a specific bacterium or sought enzymatic action or as a result of the metabolic function being tested, thereby producing a marked byproduct. These by-products are absorbed into the bloodstream and released into the patient's breath. By-products are detected by the gas analyzer in this exhalation.
[0004]
One well-known method of marking such a substrate is by replacing one of the component atoms of the substrate with an isotopically enriched atom. Such substrates and their byproducts are commonly referred to as isotope labels. One atom commonly used in such inspection procedures is a non-radioactive carbon-13 atom, which is present in a ratio of about 1.1% of naturally occurring carbon.¹³When using C as a tracer, the cleaved products produced by many such tests are:¹³CO₂It becomes.¹³CO₂Is absorbed into the bloodstream and exhaled into the patient's breath. The breath sample is analyzed before and after ingesting the marker substrate, typically in a mass spectrometer or non-dispersive infrared spectrometer.¹²CO₂Against¹³CO₂If a change in the ratio is detected, this change can be used to provide information about the presence of a particular bacterium or the desired enzymatic action, or as a measure of the metabolic function being tested. It is done.
[0005]
CO generated from the process under inspection₂The amount is the total CO that results from all of the body's metabolic processes.₂Because it accounts for a very small percentage of the output, breath testing equipment occurs naturally in the patient's breath¹³CO₂It must be possible to detect very small changes in the ratio. Typically, the device is in the exhaled breath that the patient exhaled¹³CO₂It should be possible to detect some changes in the level of one million. All exhaled by the patient¹³CO₂The content is only on the order of several hundred ppm. For this reason, the sensitivity, selectivity and stability of the gas analyzer used for the examination must be as high as possible so that accurate and speedy results are obtained.
[0006]
In addition, the device is intended to operate in a care point environment, and in this environment there is generally no continuous technician, so the device is in good working condition or used. You must have good self-diagnosis ability to determine if it is possible. For similar reasons, the instrument should also have a self-calibration capability level to correct any drift in the calibration level as indicated by the self-diagnostic test.
[0007]
Using the device in a point-of-care environment adds an additional importance to the speed at which an accurate diagnosis can be given to the patient following the examination. Therefore, in order to increase patient compliance, methods used in breath tests to analyze measurement results for significant diagnostic information are configured to provide deterministic and reliable results in the shortest possible time. Should be. In addition, the use of a simple patient and substrate preparation procedure greatly simplifies the performance of the examination at the physician's clinic.
[0008]
The entire disclosures of all publications mentioned in this and other sections of this specification are hereby incorporated by reference.
[0009]
Summary of the Invention
The present invention seeks a new method and apparatus for ensuring the accuracy, speed and reliability of breath tests. Many separate aspects of the invention are disclosed herein. An example of objects included in these perspectives is as follows:
(I) methods of patient preparation and substrate intake;
(Ii) a method for analyzing and calculating the results of a breath test so as to provide an accurate diagnosis in a minimum amount of time; and
(iii) Breath test equipment self-diagnosis function and calibration
[0010]
According to one aspect of the present invention, in accordance with a preferred embodiment of the present invention, in connection with a method for performing a breath test and a procedure employed for patient preparation prior to application of the breath test, A method is provided that speeds up the achievement of a significant result of the breath test. These methods are only possible for the first time because they are virtually continuous sampling and analysis as described in this application and as described in the prior art section. Become. In addition, a method for preparing and managing a substrate for ingestion prior to a breath test is described.
[0011]
Throughout this specification and as set forth in the claims, terms describing sampling and / or analysis, such as “virtually continuous sampling” or “virtually continuous analysis” or equivalent A descriptive expression, such as the term “substantially continuously”, means a sampling or analysis method that can be performed repeatedly at a predetermined rate. This repetition rate is high enough that multiple samplings and / or analyzes are sufficiently performed within the time it takes to determine useful clinical information from physiological effects under investigation by a breath test. Such speed is therefore largely related to the type of breath test involved. For example, in the case of a breath test for the detection of Helicobacter pylori, a significant clinical result can already be obtained in a matter of minutes, so “virtually continuous sampling” is almost every time a subject exhales. Will mean the speed. On the other hand, breath tests for liver function may take several hours before significant results are obtained. In this case, a “virtually continuous sampling” or equivalent term state may be achieved, for example, by breath sample collection and / or analysis every 30 minutes.
[0012]
This feature of sampling or analysis in practice continuously provides the present invention with many advantages over prior art methods of sampling and analyzing individual bags of exhaled breath. In practical terms, it is difficult, if not almost impossible, to implement such a conventional method “in effect continuously”. Such features also allow the present invention to provide clinically significant results faster and with a higher level of reliability than conventional methods.
[0013]
According to another aspect of the present invention, in accordance with a preferred embodiment of the present invention, breath test results are analyzed to provide an accurate diagnosis in a time significantly shorter than is possible using conventional methods. There is further provided a method of: These methods include using a method for detecting the presence of oral activity in a subject. Oral activity results from the direct interaction of the labeled substrate with bacteria in the oral cavity, regardless of the physiological condition being examined or the bacterial infection being sought. It is important to detect such oral activity and delay analysis of the collected breath until after it has subsided. Otherwise, the ability of the breath test to detect by-products of the labeled substrate released in the subject's breath after traversing the subject's bloodstream and metabolic pathways through the lung will be severely reduced.
[0014]
Yet another new preferred method for calculating the change in isotope ratio with respect to the baseline isotope ratio is disclosed. Such a method allows a more reliable test result to be obtained in situations where there is a risk of interference or excessive noise during the measurement. Another method has been described to combat drift effects in breath testing equipment. Such a drift effect may limit the ability to accurately compare a currently collected sample with a previously collected baseline sample. According to such a preferred embodiment of the present invention, the sample collected at each sampling time is not compared with the baseline sample or the external reference gas, but with the sample collected at the previous sampling time. To be compared.
[0015]
In another preferred embodiment disclosed, the detected change in isotope ratio is analyzed using a newly proposed parameter called Relative Change in Isotopic Ratio or RCIR. Is done. RCIR compares the partial changes in the ratio obtained at the present time. The resulting ratios are normalized to a wide variety of isotope ratios, each with its own advantages. Also disclosed is a method that uses different definitions for RCIR parameters depending on the progress of the resulting test results to reduce physiological or instrumental noise effects in the test results. A more accurate method of detecting the baseline level is also disclosed. Thereby, a plurality of baseline measurements are performed in order to eliminate the adverse effects that can occur due to a single departure measurement point.
[0016]
The operational function of the breath test is to determine if changes in the isotope ratio of the components of the breath sample of the subject are clinically significant in relation to the effect sought. Such criteria for determination are whether or not the isotope ratio has exceeded a predefined threshold level at or within the assigned examination time, as used in many of the prior art. It is. According to another preferred embodiment of the present invention, in order to achieve the highest sensitivity and specificity in the shortest possible measurement time, the breath test analyzer can determine whether the patient's breath isotope ratio is clinically significant. Do not use a fixed standard to determine this. Instead, this criterion is changed during the course of the test, depending on a number of factors specified during the test. These factors include, for example, the elapsed time of the test, the noise level of the instrument performing the test, and the physiological results of the test itself.
[0017]
For many conventional procedures, the measurement used to change the isotope ratio was the ratio level relative to the baseline level, but according to another preferred embodiment of the invention, the measurement is It may be the amount of change with respect to the previous measurement time other than the line level, or the rate of change of the isotope level, or any other suitable characteristic available for plotting the course of the change.
[0018]
As an example of implementing such a variable criterion, the intersection of threshold level and isotope ratio is utilized to demonstrate the advantages of these preferred embodiments of the present invention. A calculation method for more accurately using the threshold level is disclosed. Above this threshold level, the test result is assumed to be positive according to conventional methods, or below this threshold level, the test result is assumed to be negative. The new method according to a more preferred embodiment of the present invention utilizes a dynamically variable threshold. The threshold value changes with the progress of the breath test. Such dynamically variable thresholds are optionally and preferably related to the elapsed time of the test, the physiological significance of the results, the variability or quality of the results themselves, or the noise level or drift of the equipment being used. Or may be related to any combination of these factors. Furthermore, another preferred embodiment using multiple thresholds is disclosed.
[0019]
In accordance with another aspect of the present invention, there is further provided, in accordance with another preferred embodiment of the present invention, a breath test device self-diagnostic analysis method and a device system check method. According to these preferred embodiments, a method for calibrating an instrument automatically or with operator intervention according to the data being collected is disclosed. In general, when the absorption curve of a gas analyzer is accurately known, such a method determines the isotope ratio measured in the gas to be detected according to the imaginary accurate absorption curve. It is based on the assumption that it does not show any relevance. If such an association is found, this is reduced by an iterative correction method. This iterative correction method adjusts the absorption curve parameters to reduce the correlation.
[0020]
Another preferred method disclosed in accordance with this aspect of the present invention is the capnography performed at the entrance of the breath tester by comparing with the accurate measurements performed by the self-calibrating gas analyzer as summarized above. It is effective in correcting inaccuracy in measurement. Capnographic measurements are used to determine which part of the expiratory waveform is collected for analysis by the gas analyzer in the expiratory tester.
[0021]
Thus, according to a preferred embodiment of the present invention, a method for performing a breath test is used to determine when a change in an isotope ratio measurement of at least one breath sample of a subject is clinically significant. To this end, a method is provided comprising the steps of using a predefined criterion and allowing the criterion to change during a breath test. The change in the measured value is preferably a deviation of the isotope ratio from the measured value of at least one previous sample of the subject, or may be a change rate of the isotope ratio. The measured value of at least one previous sample of the subject is preferably a baseline measured value.
[0022]
According to another preferred embodiment of the invention, the criteria may be a function of the elapsed time of the test, or a function of the noise level of the device performing the test, or a function of the physiological result of the test. .
[0023]
According to still another preferred embodiment of the present invention, in the breath test method, the step of performing the first measurement of the isotope ratio of at least the first breath sample of the subject, and at least the subject Performing a second measurement of the isotope ratio of the second breath sample and a first measurement wherein the value of the second measurement is sufficient to produce a clinically significant result of the breath test A breath test method is provided which comprises the step of determining when a deviation from the value of is present, wherein a sufficient level of deviation can be varied during the breath test. The first measurement of the above-described at least first breath sample isotope ratio of the subject may be a baseline measurement. Further, the level of sufficient deviation described above is a function of time elapsed since the subject ingested the identified substrate, or a function of at least one physiological analysis of the sample, or a breath test. It may be a function of the nature of the result obtained. Such a nature of the result is preferably a function of the standard deviation of the result spread in the breath test, or a function of the noise level present in the result, or a function of the instrument drift present in the result.
[0024]
According to yet another preferred embodiment of the present invention, in the above method, a sufficient level of deviation may occupy a range of values between the upper threshold and the lower threshold, Can converge as the examination progresses.
[0025]
In any of the embodiments described above, the first measurement of the isotope ratio of at least the first breath sample of the subject is performed only after oral activity has significantly subsided.
[0026]
According to still another preferred embodiment of the present invention, in the breath test method for determining the presence of a clinically significant condition in a subject, the subject is exhaled after the effective cessation of oral activity. Measuring the change from baseline in isotope ratios in multiple samples of breath, determining a polynomial that approximates a function plot of the time of the measurement, and weighting the measurement from this polynomial A standard deviation is calculated, and for a measured value that is more than the predefined amount and exceeds the baseline, a predetermined fractional part of the measured value is taken, and a predefined amount for this. For measurements that do not exceed the baseline more often than the entire measurement is taken, and finally, the weighted standard deviation is set to a predefined level. Breath test method is provided comprising a step to ascertain whether obtain.
[0027]
Further, according to still another preferred embodiment of the present invention, in the breath test method, the step of measuring the isotope ratio of at least the first breath sample of the subject, It consists of identifying this when it shows a deviation from the baseline measurement that is sufficient to produce a clinically significant result, where the deviation consists of uncertain upper and lower threshold bands, The breadth is the elapsed time of the breath test, the standard deviation of the physiological spread of the results, the dynamic characteristics of the physiological change in the isotope ratio, the number of time points measured in the breath test, and the environmental conditions that exist during the breath test And a breath test method associated with at least one of the parameters selected from the group consisting of noise and / or drift levels of the device performing the breath test.
[0028]
According to yet another preferred embodiment of the present invention, in a method for determining the reliability of a breath test, a step of obtaining a result from the breath test, a level of instrument noise and / or drift, a physiological result Reliability by combining at least one of the criteria selected from the group consisting of standard deviation of spread, dynamic characteristics of physiological changes in isotope ratio, and elapsed time since ingestion of labeled substrate A method is provided comprising the steps of defining a parameter and using the reliability parameter to evaluate a breath test result according to a predefined reliability criterion. The reliability parameter may be used to determine when the test should be terminated.
[0029]
Furthermore, according to another preferred embodiment of the present invention, in a method for calibrating a breath test apparatus without the need for externally supplied calibration means, the isotopic composition of gas components in a plurality of subject samples is provided. A method is provided comprising the step of continuously measuring the body ratio, and determining the correlation between the isotope ratio of the gas component in the sample and the concentration of the gas component. Such a calibration method requires neither operator involvement nor active subject involvement.
[0030]
According to still another preferred embodiment of the present invention, in a method for calibrating a breath test apparatus without the need for externally supplied calibration means, gas components in a plurality of subjects' samples are obtained. A method is provided comprising the steps of measuring the isotope ratio substantially continuously, and determining the correlation between the isotope ratio of the gas components and the environmental conditions present during the breath test.
[0031]
According to yet another preferred embodiment of the present invention, a result obtained with a breath sample of a plurality of subjects does not show any significant change in the isotope ratio of a particular gas component measured in the sample. A method is provided for calibrating breath test equipment by analyzing and thereby determining the correlation between the isotope ratio and the concentration of gaseous components in the sample.
[0032]
Furthermore, according to another preferred embodiment of the present invention, the results obtained with a plurality of breath samples collected from a subject are analyzed, whereby the isotopes of specific gas components measured in the samples By determining the correlation between the ratio and the concentration of the gaseous component in the sample, a method is provided for calibrating the breath test equipment.
[0033]
According to still another preferred embodiment of the present invention, in the following method for calibrating a breath test device, (a) collecting a breath sample containing a specific gas component, and (b) in the sample Measuring the concentration of the specific gas component, (c) determining the isotope ratio of the specific gas component in the sample, and (d) diluting the sample so that the concentration of the specific gas component changes. And (e) a step of re-determining the isotope ratio; (f) a step of obtaining measurements of samples at a number of different concentrations by repeating steps (d) to (f); A method comprising: determining a correlation between an isotope ratio and a concentration of a sample of concentration; and (h) adjusting a calibration of the breath test equipment to reduce any correlation found. Provided.
[0034]
According to yet another preferred embodiment of the present invention, in a method for correcting a change in calibration of a gas analyzer to determine an isotope ratio between a first component and a second component of a gas sample, A step of measuring the concentration of the first component by transmission measurement, and a step of calculating the concentration of the second component from the measured concentration of the first component by assuming a predetermined ratio between the components. And by correcting the transmission measurement performed on the second component, the concentration derived from this transmission measurement is substantially equal to the concentration calculated in the previous step from the measured concentration of the first component. A method comprising the steps of: The component of the gas sample is preferably an isotope component.
[0035]
According to yet another preferred embodiment of the present invention, a measured isotope ratio of gas components in a breath sample in a method for retrospectively correcting breath test results resulting from imprecise calibration effects. Performing a calibration procedure according to one of the methods described above to determine the existence of a correlation between the gas and the concentration, and a corrected parameter of the gas absorption curve to eliminate the correlation. Provides a method comprising correcting the calibration of the device and recalculating the data of the previous breath test using an absorption curve having the corrected parameters.
[0036]
Furthermore, in accordance with another preferred embodiment of the present invention, in a method of calibrating a capnograph probe effective for measuring an input breath waveform with a breath test device, the accumulated accumulated breath collected according to the measured capnograph waveform. Measuring the concentration of the accumulated breath sample in the gas analyzer of the breath test instrument; and measuring the concentration of the capnograph probe with the concentration measured by the gas analyzer. As provided, a method is provided that comprises correcting the calibration of the capnograph probe.
[0037]
Furthermore, according to another preferred embodiment of the present invention, a breath test device is provided. This breath test device monitors the changes in the isotope ratio of the gas in the breath sample exhaled from the subject virtually continuously and, according to the current results of the test, the test has clinically significant conclusions Determine that. The breath test device preferably provides a signal, such as a visible signal or an audible signal, to indicate that a clinically significant result of the breath test has been determined.
[0038]
According to yet another preferred embodiment of the present invention, the breath test apparatus described above is such that the test conclusion is substantially independent of the dynamic physiological effects that occur in the subject as a result of background conditions. It may be like this. These background conditions may be the result of treatment with medication or the result of food intake prior to performing a breath test. As a result, the use of the breath test apparatus described above can eliminate the need for fasting before the test by the subject.
[0039]
Furthermore, according to another preferred embodiment of the present invention, when using this breath test device, the conclusion of the test of a subject treated with gastrointestinal medication is substantially continuous with the change in isotope ratio. Can be obtained more reliably or more quickly, or more reliably and more quickly than using a corresponding breath test that is not frequently monitored.
[0040]
According to yet another preferred embodiment of the present invention, does the current result of the test allow a positive result to be determined even if the isotope ratio does not clearly exceed a predetermined threshold level? Or, if the isotope ratio exceeds a predetermined threshold level, the current result of the test allows to determine a negative result.
[0041]
Furthermore, according to another preferred embodiment of the present invention, a method for determining whether the correct isotope labeling substance kit is used for a specific breath test is selected to have an immediate short-term effect on the breath test. A method is provided comprising adding a marker element to a substance and providing a breath test device comprising a detector for the marker element. In addition, the breath test device is also comprised of an authorization mechanism that allows the instrument to perform an analysis of the results of the breath test sample only after detection of the marker element. Also good.
[0042]
In accordance with yet another preferred embodiment of the present invention, a method for determining when the effect of oral activity subsides during a breath test is required to detect the physiological effect during the breath test. Determining the characteristic time, monitoring the change in the isotope ratio in the breath sample collected from the subject following ingestion of the isotope-labeled substrate, and within a time shorter than the characteristic time Detecting the presence of significant peaks exceeding a predetermined minimum threshold level generated in the ratio.
[0043]
According to yet another preferred embodiment of the present invention, a method in a breath test procedure for determining a baseline level of isotope ratio of gas components in breath exhaled from a subject prior to ingestion of an isotope labeled substrate , The step of measuring the first baseline point, the step of evaluating the reliability of the measured value, and the reliability of the measured value of the first baseline point is determined to be insufficient Performing a second measurement of at least one additional baseline point.
[0044]
According to yet another preferred embodiment of the present invention, a method in a breath test procedure for determining a baseline level of isotope ratio of gas components in breath exhaled from a subject prior to ingestion of an isotope labeled substrate A method comprising measuring at least first and second baseline points is provided. Preferably, the average of the two points is used as the baseline value when the first two of the at least two baseline points are within a predetermined range of each other. Alternatively and preferably, the third baseline point is measured if the first two of the at least two baseline points are not within a predetermined range of each other. In addition, points that are further away from the third baseline point are discarded if the first two of the at least two baseline points are not within a predetermined range of each other.
[0045]
Further in accordance with another preferred embodiment of the present invention, there is provided a method for determining changes in isotope ratios of at least a first, second and third gas samples collected at different times. A method is provided in which the change in ratio is determined by measuring the isotope ratio of the second sample relative to the first sample and relative to the third sample.
[0046]
According to yet another preferred embodiment of the present invention, a method for reducing the effects of reducing the effects of changes in operating conditions of a gas analyzer on the isotope ratio measured in a series of at least three gas samples. Measuring the isotope ratio of at least one sample relative to a sample collected before the at least one sample and a sample collected after the at least one sample. Method is provided.
[0047]
According to yet another preferred embodiment of the present invention, a method is provided for ascertaining changes in the isotope ratio between the first and second gas samples. The method includes measuring a isotope ratio of a first sample, measuring the isotope ratio of a second sample, determining a difference between the isotope ratios, Dividing by one of the ratios, and adding this change to the previous change determined between the previous first and second samples.
[0048]
According to yet another preferred embodiment of the present invention, in a method for determining changes in isotope ratios of at least first, second and third gas samples collected at different times, an isotope ratio is provided. Are determined by measuring the isotope ratio of the second sample in relation to the first sample and in relation to the third sample, and each change in isotope ratio is determined by the method described above. Is determined by.
[0049]
According to yet another preferred embodiment of the present invention, in a method for ascertaining a change in isotope ratio between a first and a second gas sample, (a) measuring the isotope ratio of the first sample; (B) measuring the isotope ratio of the reference sample; (c) calculating a first difference between the first two isotope ratios; and (d) the isotope of the second sample. Measuring the ratio; re-measuring the isotope ratio of the reference sample; calculating a second difference between the second two isotope ratios; and (g) first and second And subtracting one of the differences from the other.
[0050]
According to yet another preferred embodiment of the present invention, in a method for ascertaining a change in isotope ratio between a first and a second gas sample, (a) measuring the isotope ratio of the first sample; (B) measuring the first isotope ratio of the reference sample; and (c) determining a first difference between the isotope ratio of the first sample and the first isotope ratio of the reference sample. Calculating, (d) normalizing the first difference with respect to the first isotope ratio of the reference sample, (e) measuring the isotope ratio of the second sample, (f ) Measuring a second isotope ratio of the reference sample; and (g) calculating a second difference between the isotope ratio of the second sample and the second isotope ratio of the reference sample. And (h) normalizing the second difference with respect to the second isotope ratio of the reference sample, and (i) of the normalized difference By subtracting towards the the other, the method comprising a step of ascertaining a change in isotope ratio is provided.
[0051]
According to still another preferred embodiment of the present invention, in a method for determining changes in isotope ratios in a plurality of breath samples of a subject by a breath test, (a) collecting a reference sample of breath; (B) determining an isotope ratio of a first breath sample of the plurality of breath samples by comparing with an isotope ratio of a reference breath sample; and (c) a second of the plurality of breath samples. Determining an isotope ratio of the exhaled breath sample by comparing with an isotope ratio of the reference breath sample; and (d) between a first breath sample and a second breath sample of the plurality of breath samples. And determining the determined change in isotope ratio.
[0052]
The term “calibration check” as used throughout the specification and claims refers to the measurement of the absolute calibration of the isotope ratio measured by the breath tester. This absolute calibration measurement is made with reference to a zero baseline level by using a calibration check gas with a known isotope concentration or ratio input to the instrument from an externally supplied container. Is called.
[0053]
The term “system check” is commonly used throughout this specification and claims to describe a method for determining the precise functioning of a measurement system in many ways. An example of this function is the primary calibration of a gas analyzer, but it is also not limited to radiation source stability, input capnograph calibration, gas handling system, and collected exhaled breath samples. Also included are functions such as an intermediate chamber system to enable and detector operation.
[0054]
Because the calibration check is part of the system check, there are some places where these terms are used redundantly for discussion purposes. The term “calibration” of the instrument, in other respects, is used in this specification and claims to correct the parameters of the absorption curve used for infrared absorption measurements, so that these parameters can drift or occur within the instrument. Usually used to describe the process of compensating for changes caused by the environment. According to this terminology, the calibration procedure used in this application is different from the calibration check procedure and typically does not utilize an externally supplied gas with a known isotope concentration or ratio. Relevant to checking for internal discrepancies in results obtained with actual measurements performed by the breath tester. The usual discrepancy revealed is an incorrect correlation between the measured isotope ratio and the gas concentration. This will be described in detail later.
[0055]
The present invention can be understood and appreciated more fully from the following detailed description, taken in conjunction with the drawings in which:
[0056]
Detailed Description of the Preferred Embodiment
Overall structure and function of breath test equipment
Reference is made to FIGS. 1 and 2, which are schematic diagrams showing parts of a prior art breath test apparatus. This type of equipment can incorporate many of the methods and apparatus of the various embodiments of the present invention. These drawings are taken from the pamphlet of International Publication No. 99/14576 (WO99 / 14576) described in the background section of this application. FIGS. 1 and 2 are presented only to illustrate and clarify certain aspects of the present invention, and the method and apparatus of the present invention are suitable for use in breath testers of the type shown in FIGS. It should not be construed as limited. The components and functions of the breath tester shown in FIG. 1 and FIG.¹³CO₂The use of the breath test will be described.
[0057]
Referring to FIG. 1, which is a schematic block diagram of the components of an exhalation tester, the exhalation tester includes an intermediate chamber apparatus for accumulating and handling exhalation samples to bring them to a desired concentration for analysis. Is incorporated. A subject 1 undergoing a breath test breathes and breathes into the nasal cavity or oral cannula 2. An expiration sample is input into the expiration sensor module 3. The exhalation sensor module is an input capnograph probe and the function of this probe is to monitor the waveform of each sample exhalation and determine which part of each exhalation accumulates and which part is discarded during analysis. The intermediate chamber gas processing device 4 having a device consisting of a sensor and a solenoid valve can be operated to introduce a portion of the sample exhalation into the sample storage chamber 5 or lead it into the chamber if not needed. As soon as sufficient gas is collected at the desired concentration, the sample gas is transferred from the storage chamber 5 to the NDIR molecular correlation spectroscopy cell 6 for measurement of the isotope concentration in the gas. A computer-based control system receives and processes the results of the absorption measurement, calculates the isotope ratio of the sample, and more generally controls the complete operation of the intermediate chamber device.
[0058]
Reference is made to FIG. 2 showing in perspective a prior art NDIR molecular correlation spectrometer of the type used in the breath tester shown in FIG. The analysis chamber is incorporated in the aluminum block 10. Two chambers are used per isotope analysis: one sample chamber and one reference chamber. Having an end visible within the end plate 12 of the analyzer block 10;¹³CO₂The minority isotope chamber 11 for the¹²CO₂It is significantly longer than the chamber 13. A thin shutter 14 is used to switch the measurement between the sample channel and the reference channel. In the embodiment of the spectrometer shown in FIG. 2, the isotope-specific source 15 and the absorption chambers 11, 13, such that the output beams from all four channels are directed by the light cone 15 to a single detector 16. Has been guided.
[0059]
Self-diagnosis and calibration
1. self-diagnosis
Since the device is continually operating in a point-of-care environment where there are no technicians, the device is a good indicator of whether it is in good working condition and usable. Must have self-diagnosis ability. In connection with the function of the diagnostic system, there are five main levels of function: a two level diagnostic function and a three level series of actions or corrective actions:
(A) Accumulation of historical database of functional parameters of equipment operation such as noise level, drift, correlation of irrelevant results, etc.
(B) Recognition of the existence of the problem and evaluation of its severity. Problems are identified based on parameters that exceed the limits of the instrument specification or based on changes in the system as compared to the past performance of the instrument.
When the existence of a problem is established at level (b), the problem is handled according to levels (c)-(e). The level reached is related to the severity of the problem identified and the impact on the measurement performed. The levels are listed in order of increasing severity:
(C) Automatic application of corrections to the measurement being performed
(D) Alarm output that equipment maintenance or calibration is required
(E) Complete disabling of equipment
[0060]
As an example of the different functional significance of each of these levels, the results of each of the above five levels are shown using the influence of noise contained in the measured values.
(A) Measurement values are constantly monitored, and results for a specific period going back in the past are stored in the database. Noise level results are recorded for actual measurement variability and for various operating parameters of the instrument such as lamp or detector noise.
(B) The noise level is checked for deviations from the reference or deviations from past behavior. If the random noise is below a predetermined critical level, the diagnostic method does not consider the noise as problematic enough to prevent achieving accurate measurements. In other aspects, excessive correlation noise always leads the instrument to one or the other of the recalibration modes, as will be discussed later in the instrument calibration section.
[0061]
Depending on the type of measurement being performed, what constitutes a critical noise level is identified. A measurement that clearly represents the patient's health status and shows a strong positive or strong negative result can tolerate a higher level of random noise than a measurement that gives a result very close to the threshold level. For results close to the threshold level, a noisy signal can lead to false positive or false negative results, thus requiring a lower critical noise level. Thus, the high reliability of the breath test measurement can be determined in relation to the conditions placed during the breath test itself.
[0062]
The instrument diagnostic system is preferably configurable to output measurement reliability parameters. This measurement reliability parameter is a combination of many or all of the operating parameters that affect the measurement reliability as described above. This measurement reliability parameter may be, for example, a predetermined combination of proximity to the breath test measurement result threshold, the noise level encountered during the measurement, and the level of the result itself. Thus, the measurement reliability parameter, by its function, defines what constitutes an excessively high noise level, and such a definition is in accordance with the results being obtained when the definition is being made, Done.
[0063]
Such parameters are also preferably capable of being output along with the test results to give the physician additional information regarding what confidence level is attributed to that particular test result.
[0064]
Throughout this specification, the terms “positive” and “negative” mean that the patient exhibits a high DoB (delta over baseline) isotope ratio or a non-high DoB isotope ratio, respectively. Used for. Of course, whether high DoB indicates normal health or vice versa depends on the particular test being performed. For example, H.C. In the case of a breath test for H. pylori, high DoB may be associated with the presence of bacteria. On the other hand, for example, in the case of a breath test for liver function, a low DoB may indicate a liver disease state.
(C) If the noise level is high but not high enough to obtain a significant measurement, the diagnostic system preferably applies a compensation procedure to the measurement. A commonly applied compensation procedure is achieved, for example, by increasing the average measurement time of the sample currently undergoing analysis in a gas analyzer.
[0065]
Another compensation procedure for excessive noise in instrumental or physiological test results reduces the threshold level bandwidth for defining positive results to a low level as discussed in more detail later herein. This is done by associating. Such a compensation procedure directly affects the measurement reliability parameter output by the instrument.
[0066]
Yet another compensation procedure for excessive noise uses criteria to terminate the test. If the noise level is such that the final decision regarding the conclusion of the test is hidden by noise fluctuations, it is preferable to make a decision to extend the test in order to obtain a more definitive result that exceeds the noise level.
(D) This level of warning provides a measurement with a good confidence level that the compensation mechanism in the equipment can tolerate as soon as the situation of level (c) is encountered or at a higher noise severity level. It is preferably activated depending on whether it is successful. At this level, output is preferably provided by the diagnostic system to alert the user that equipment maintenance or calibration is required so that noise sources can be identified and eliminated.
(E) If the noise level becomes excessive and the compensation procedure cannot achieve an accurate measurement, the state of level (e) is reached. At such a stage, the diagnostic system preferably disables the device. This is because in this case there is a risk of producing an incorrect result.
[0067]
2. Equipment check
The breath tester, according to a more preferred embodiment of the present invention, can perform all individual checks of key device functions by performing a pseudo breath test on a calibration gas supply sample. Specifically, the calibration state of the device is checked. Such a check is performed in conjunction with the present PCT application No. PCT / IL00 / 00338 “Gas Analyzer Calibration Checking Device” specification (several of the applicants filed applications of the present invention). As described in International Publication No. 00/74553 (WO00 / 74553) pamphlet), it can be suitably carried out in a number of ways. The entirety of the above specification is incorporated herein by reference. The sample may be, for example, two physically separate samples consisting of a gas mixture supplied in a calibration cylinder. Each gas mixture has a known total CO₂Concentration and known¹³CO₂/¹²CO₂And isotope ratio. Using two separate calibration check gases provides information about the absolute gain of the instrument, thereby knowing the location of the two absorption curves. Such information is then¹³CO₂It can be used to confirm the true position of the absorption curve. this¹³CO₂The absorption curve is assumed to be constant during the instrument calibration procedure described below.
[0068]
Alternatively and preferably, a single gas with a known gas mixture is used, and the intermediate chamber of the instrument may be used to generate separate samples, each having a different concentration. Gases with unknown properties may be used and the intermediate chamber of the instrument is used to generate separate samples, each sample having the same isotope ratio and a different concentration.
[0069]
As an alternative to checking the calibration status by analyzing an external gas source having a known or fixed isotope ratio, a pseudo breath sample having a different isotope ratio from one gas sample may be used. By using the breath simulator device to be generated, the pseudo breath test calibration check can be suitably achieved. The above-mentioned International Publication No. 00/74553 (WO00 / 74553) pamphlet describes a suitable breath simulator device. The parameters of the simulated breath sample are the parameters encountered during normal operation of the actual breath test, such as flow rate, “breathing” rate, CO 2₂Percentage, and¹³CO₂/¹²CO₂It is the same as the ratio.
[0070]
Checks are preferably made for instrument calibration, hardware, software, pneumatic characteristics and mechanical characteristics. Each device check may involve two levels: verification and correction. The former confirms that the device is functioning as specified, and the latter corrects the reading according to the output of the diagnostic system. Alternatively and preferably, if the device check procedure identifies a need for calibration, a calibration can be performed later.
[0071]
In addition, it is preferred that the check be performed with an internet connection to the central service center to assist in online diagnostics or periodically for routine service checks and maintenance.
[0072]
2.1 Processing system self-check
According to another preferred embodiment of the invention, the device incorporates a self-checking function. This self-check function ensures the correct operation of the processing software and processing hardware in watchdog mode. Such a function preferably consists of a secondary microprocessor having associated software separate from the main equipment software. The main system microprocessor generates a predetermined composite output sequence at regular intervals. The secondary microprocessor analyzes this sequence and if a deviation from a predetermined shape is detected, the watchdog system issues a warning and closes the main processor. The PC is then restarted under the control of the secondary processor and the reason for the malfunction is investigated.
[0073]
2.2 Hardware self-check
A complete device preferably performs a self-check of its hardware, and the software is directly involved in operating the hardware. Some of these checks require the use of a known charge of gas in the reference and absorption chambers. Other checks are on the function of the hardware components that operate independently of the specific measurement being made, and therefore the presence of a calibration gas sample is not required.
[0074]
About 60 parameters are preferably used to characterize the operation of the device. Some of these parameters are monitored continuously during operation of the device as a real-time diagnostic function. Most of these parameters are monitored only between tests or when the instrument switches from standby mode to ready mode. Of the approximately 60 parameters, 16 are preferably defined as critical parameters, and deviations from predetermined tolerances become obstacles during use of the system. Some of the critical parameters are:
(A) Light source stability in relation to time
(B) Reference cell absorption check
(C) Shutter operation between the reference channel and the sample channel
(D) Input capnograph operation
(E) Intermediate chamber operation-pneumatic and electronic devices
(F) Feasibility check of the obtained δ value (eg a negative value or a value that has a large change during the following exhalation activates the critical parameter flag) of the system to which these parameters are associated The components are shown in FIGS. 1 and 2, and more particularly in WO 99/14576. FIG. 1 and FIG. 2 are adopted from this brochure.
[0075]
In order to illustrate the use of critical parameters, a test for light source stability will be described in more detail. At the first switch-on, the lamp intensity I is monitored in the reference channel as it is transmitted by optical fiber from the lamp to the detector, thereby determining lamp stability during warm-up. When the intensity time difference dI / dt falls below a predetermined level, the lamp is considered stable and an enable signal is output to the device controller. If the desired stability level is not reached, the device waits for stability to be achieved for a predetermined time. After this time has elapsed, a lamp maintenance request is displayed and the device cannot operate. Similarly, during operation, when dI / dt exceeds a predetermined level, a disable signal is provided to the device.
[0076]
3. System calibration
In accordance with another preferred embodiment of the present invention, the breath test apparatus can perform four levels of calibration. The action of these calibrations ensures that the measured difference in isotope ratio is accurate at an absolute level. Such a calibration procedure is performed by modifying the absorption curve parameters used in the gas analyzer to convert light transmittance to gas concentration. In this way, the calibration procedure compensates for drifts occurring in the absorption curve, whether due to environmental changes or due to changes in equipment components. These absorption curve changes are the most common cause of inaccurate calibration in such breath tester devices. These calibration procedures are performed at the software level within a routine for converting a series of light absorption measurements into isotopic ratio differences. In this regard, these calibration procedures can be distinguished extensively from the calibration check procedures described above. The calibration check procedure checks the absolute accuracy of the measured isotope ratio by using a gas with a known isotope ratio.
[0077]
The four preferred levels of calibration are as follows:
3.1 Soft calibration
3.2 Self-calibration
3.3 Patient calibration
3.4 Service calibration
The first three of these procedures are performed automatically and continuously without requiring operator or patient intervention. The first three of these inspection procedures and one embodiment of the service calibration procedure are different from any prior art gas analyzer calibration procedure. In the prior art, the calibration procedure uses the subject's own exhalation to determine whether calibration is necessary and to perform the recalibration procedure itself. Procedures are known in which an exhaled breath sample bag provided by an operator or nurse is used as a calibration gas sample, but such a sample is similar to an unknown calibration gas supplied externally, Of course, it requires operator guidance and intervention.
[0078]
In addition, the first of these calibration procedures is an ongoing process that works continuously in the background. As a result, trends in instrument calibration can be identified better than would be possible with any external calibration. Such external calibration relies on procedures performed at specific times that may be accidentally encountered at the moment when a temporary change or abnormal event occurs in the instrument.
[0079]
The second preferred embodiment of the service calibration procedure certainly utilizes an externally supplied gas sample for the calibration procedure. Of the calibration procedures described above, all but soft calibration are different CO 2 derived from gas samples with the same isotope ratio.₂Based on the measurement of the relationship between each isotope ratio measured in a gas sample of concentration.
[0080]
3.1 Soft calibration
This preferred calibration method is software based and works continuously in the background of the system. Moreover, in this case, no patient or operator intervention or involvement is required. Such a procedure preferably continuously monitors the breath sample analysis results obtained from subjects with results close to baseline. For example, H.C. In the case of the H. pylori breath test, this means a subject found to be negative. According to a preferred embodiment, the system software monitors the results of all patients who have shown a negative response to a breath test performed over the past 2-3 days. The measurement points used for this test result from the measurement points obtained during the baseline measurement performed prior to ingestion of the isotope-labeled substrate and possible interactions between the labeled substrate and bacteria present in the oral cavity. Measurement points obtained after any oral activity ceased.
[0081]
Each of these negative patients provides a breath sample. Each breath sample is typically a slightly different random level of CO.₂Because of the concentration, each absorption measurement is made at a slightly different point on the absorption curve. 2.3% to 2.7% CO₂A breath sample having a concentration is preferably used, whereby the deviation of the absorption curve is checked over a range of values, not just one point.
[0082]
This is in contrast to normal measurement procedures. For normal measurement procedures, the use of a constant concentration in each test is an important factor that reduces the sensitivity of measurement accuracy to instrument calibration conditions. As long as all absorption measurements are made at one concentration level in a single test, any drift in the isotope absorption curve will affect the entire measurement equally evenly, so any lack of calibration is secondary Will be affected. Due to changes in absorption curve,¹³CO₂/¹²CO₂The measurement error of this ratio is certainly possible, but since this error appears equally in all measurements, it does not have a primary effect on the detected ratio change.
[0083]
For soft calibration procedures, samples tested from a single negative patient must have the same isotope ratio, despite having different concentrations, within the noise limits of the measurement. But the measured ratio is not the same, but the sample CO₂When showing a correlation with concentration, this is an indication of a change in the absorption curve from a correctly calibrated value. The “soft calibration” method in this case preferably corrects the shape or position of the absorption curve, thereby returning the instrument to the calibration state. This calibration state is indicated by the lack of correlation between isotope ratio and concentration. A method for performing the correction will be described later. After correction of the shape of the absorption curve, all data for patients who were negative in the last 2-3 days were checked again for correlation between concentration and isotope ratio, which resulted in a successful recalibration procedure Is confirmed. This success is indicated by a reduction in the aggregate correlation level for all data. Since this calibration procedure is performed continuously in the background, it maintains a constant recalibration of the instrument for shifts in the absorption curve within the working concentration range.
[0084]
If, during a soft calibration procedure for a particular patient, no significant correlation is found between the concentration with the isotope ratio measured at different values, the system is considered correctly calibrated and No adjustment is made at that time.
[0085]
In addition to the correlation between isotope ratio and concentration, the soft calibration process is programmable to investigate the correlation between isotope ratio and other functions that may affect instrument calibration. It is preferable. Among such functions are environmental conditions such as the temperature present in the device. This temperature has a significant effect on the absorption curve.
[0086]
3.2 Self-calibration
This measure is also performed automatically without operator or patient involvement, as with soft calibration. However, this procedure differs from the soft calibration procedure and preferably involves both instrument hardware and processing software. If two conditions are met, the procedure is preferably programmed to start at the end of the breath test. These conditions are the following two:
(i) the tested patient showed a negative result; and
(ii) The total percentage of carbon dioxide in the patient's alveolar breath is fairly high, preferably 4% or more.
High CO that would be obtained by collecting only alveolar exhalation₂The operation of the intermediate chamber is adjusted to provide a single accumulated sample having a concentration, eg, 3.5% concentration. This sample is measured for isotope ratio and then diluted by an intermediate chamber system to provide preferably two additional samples having a low concentration, eg 3%, 2% concentration. Each of these samples is also measured for isotope ratio.
[0087]
In order to provide more points to evaluate the calibration, the self-calibration procedure may also use data results obtained around the preferred operating point of the absorption curve taken from the patient's previous exhalation. preferable. A total of 5 points: 3 points from a single sample of high concentration and its diluted derivative, and 2 points from the last negative breath taken during the test Is preferably used. The purpose of extending the sample concentration in this way is to cover as much of the concentration range of the absorption curve as possible.
[0088]
The isotope ratio is checked at each of the five concentrations. The measured isotope ratio is the same because each sample is from the same accumulated breath sample or from another breath taken from the same negative patient at a time close to the time of collection of the accumulated breath sample It should be. Any difference indicates a drift in the absorption curve as described above, and thus the recalibration procedure is initiated to eliminate such a correlation between isotope ratio and concentration.
[0089]
Since this self-calibration procedure is performed after completion of the breath test, for example when the next patient is ready for his / her test, this self-calibration procedure effectively saves any additional equipment dead time. It is not necessary.
[0090]
3.3 Patient calibration
In situations where the instrument is not in continuous use or has not been used for a predetermined period of time, or if the initial system check detects the need for immediate calibration, the system is a more preferred implementation of the present invention. According to the example, the implementation of the patient calibration procedure is automatically started. In this procedure, the first few breaths of the patient, prior to administration of the labeled substrate, are collected and diluted by an intermediate chamber to provide a number of consecutive samples having different concentrations. Each of these samples should have the same isotope ratio. This is because they are all taken at the baseline level from the same patient. The calibration procedure then adjusts the absorption curve as described above until the ratios obtained from the different concentrations of samples are all essentially the same. A preferred criterion for determining whether recalibration is necessary is, for example, a CO of 3% to 1.5%.₂Regarding the change in concentration, the isotope ratio changes by less than 3δ (ie less than 30 ppm).
[0091]
This procedure is less desirable in terms of patient patience than a self-calibration or soft calibration procedure because it increases the time that the patient has to provide an exhalation sample, but the sampling time is slightly longer. Apart from, this procedure also does not involve conscious patient or operation involvement.
[0092]
Using any of the three calibration procedures described above, according to another preferred embodiment of the present invention, newly found calibration data is used to correct previously performed test results. It is possible. For example, if the test results show a strong correlation between the measured ratio and concentration, and the calibration calculation procedure corrects the absorption curve, such correction is not only available for future measurements, Past measurements can also be corrected.
[0093]
A lack of correlation is revealed at the end of a test, but if the data available from this test is insufficient to fully calibrate, or there is sufficient exhalation available from this test If it does not cover the full range, the system recommends performing a patient calibration procedure and accumulates data that is accurate enough to make a retrospective calculation of the results of this test. According to this preferred embodiment, the patient only needs to give some more exhalation at the end of his examination and then released.
[0094]
3.4 Service or operator calibration
This is similar to the patient calibration procedure. Exceptions, however, are made when the need to perform calibration becomes apparent, or is required by an external cause, such as a subsequent service, or to maintain the instrument in an accurate state This procedure is to be initiated by a technician or operator when commanded after expiration of the maximum time between calibrations. For this procedure, the gas is the operator's breath sample used by the method described above, or external to the calibration gas as included in the periodic system calibration check described above in the system calibration check section. Can be used from container.
[0095]
3.5 Calibration correction method
It is desirable that recalibration is required when the physical parameters of the gas analyzer are changed so that the absorption curve is different from the absorption curve that existed when the instrument was last calibrated. This change in the absorption curve means that the function of correlating the absorption cell transmittance with the detected gas concentration has changed. In such situations, recalibration is preferably achieved by correcting the absorption curves and returning these absorption curves to their correct form. This makes the specific detected intensity equivalent to a given gas concentration. The recalibration process is accomplished by another preferred embodiment of the present invention called a calibration correction method. The stage of this calibration correction method will now be described. First, all hardware-involved calibrations such as self-calibration, patient calibration or service calibration are described, followed by soft calibration, which is a procedure using only software.
[0096]
3.5.1 Regular calibration procedure
Reference is made to FIG. 3, which is a flow diagram schematically illustrating the main steps of a calibration procedure according to another preferred embodiment of the present invention. The input data for the procedure is a series of¹²CO₂Transmittance {T₁₂}_i400 and a series¹³CO₂Transmittance {T₁₃}_i401. These are known from measurements of different samples of the same gas, and each sample has a different concentration C₁₂have. Since all of these measurements are from the same gas sample, the isotope ratio for all concentrations should be constant.
[0097]
T₁₃For each value, the equivalent concentration C₁₃Is the value of a given C, as shown in step 402₁₃Absorption curve T₁₃= F₁₃(C₁₃) Value T₁₃Is known by adapting
[0098]
Where CO to be used₂Within the working range of concentrations, the absorption curve corresponding to both isotopes T (c) has the form:
T (c) = y₀  + A exp (-c / t)
Can be described with good accuracy by a single index. T (c) is the transmittance in relation to the concentration c, and y₀, A and t are parameters defining the absorption curve.
[0099]
further,¹³CO₂Absorption curve¹²CO₂It is significantly more stable than the absorption curve and its parameter y₁₃, A₁₃And t₁₃However, it has been found empirically that it is considered to be virtually unrelated to changes in environmental conditions. Therefore,¹³CO₂The absorption curve is considered as a fixed function.
[0100]
The calibration procedure preferably consists of the following steps:
1. In step 402, the measured {T₁₃}_iValue, known¹³CO₂By inserting into the absorption curve, a series of {C₁₃}_iGet the value. C₁₃= F^-1 ₁₃(T₁₃).
2. Next, in step 404, isotope ratios R, C₁₂= C₁₃By using / R, a series of unknown {C₁₂}_iCan be created. The value of R used is the natural isotope ratio R = (C₁₃/ C₁₂)_naturalCan be approximated without loss of convergence efficiency of the calibration process used.
3. In step 406, {C₁₂}_iNewly generated values and {T₁₂}_iTo the new parameter y₁₂, A₁₂And t₁₂Used to identify. These parameters are C₁₂Characterize the current state of the absorption curve more accurately. This is preferably done by an optimal summation, for example a “minimum mean square error” as is well known to those skilled in the art.
4). Newly generated {C₁₂}_iValue of the new C₁₂By inserting into the absorption curve, a series of corrected transmittance values {T_12c}_iGet 408. As expected from the method of calculating these corrected transmittance values, a constant isotope concentration ratio R is obtained as necessary.
5. In step 410, the initial input transmittance value {T₁₂}_iAnd new corrected transmittance value {T_12c}_iAnd calculate each concentration {C₁₂}_iWith respect to the normalized error ΔT₁₂= (T_12C-T₁₂) / T₁₂Get. Thus, a series of these values {ΔT₁₂}_iGet.
6). In step 412, {ΔT₁₂}_iAnd the new value of {C₁₃}_iAnd the known optimal polynomial ΔT₁₂= P (C₁₃). The order of the polynomial is related to the number of concentrations used as input data and is typically 3-5.
[0101]
As a result of the above calibration procedure, C₁₂A new absorption curve for calculating the concentration is obtained. Thus, using this polynomial, each newly measured T₁₂Is corrected to a more accurate value. New correction function ΔT₁₂= P (C₁₃) Ensures that zero delta values are obtained between gas samples with different concentrations but with the same isotope ratio, depending on the method from which it is derived.
[0102]
According to another embodiment of the calibration procedure, a simplified calculation method can be used. In the case of this calculation method, the correction polynomial P (C₁₃) Is the new C₁₂Instead of generating an adsorption curve,¹³CO₂C obtained from the absorption curve₁₃The value of can be used to change directly. According to this method, step 406 of FIG.¹²CO₂The absorption curve is also¹³CO₂As with the absorption curve, it is assumed to be fixed. However, as mentioned above, the advantage of using the full calculation procedure is that C₁₂When the change in the absorption curve follows, it is possible to obtain a more obvious physical reality of what is changing.
[0103]
3.5.2 Soft calibration procedure
The soft calibration is a correction polynomial function ΔT₁₂= P (C₁₃) Differs from full calibration only in that it is optimized. C₁₃And C₁₂The absorption curve corresponding to is left untouched.
[0104]
This preferred procedure is based on a series of histories from tests with negative results from samples taken before ingestion of the labeled substrate (baseline results) or after any oral activity subsides.¹³CO₂Transmittance {T₁₂}_iAnd history¹³CO₂Transmittance {T₁₃}_iAnd need to enter. Transmittance is grouped by the test from which they were obtained.
[0105]
This procedure has the following steps similar to those used for the regular calibration described above:
1. Current C₁₃, C₁₂Using the absorption curve and the latest known correction polynomial, calculate the delta and concentration corresponding to the input transmission, {C₁₃}_iDetermine concentration and delta.
2. {C₁₃}_iThe value of C₁₂= C₁₃/ R inserts a series of {C_12c}_iCreate R is constant and can be set equal to the natural ratio.
3. CO₁₂Absorption curve and {C₁₂}_iAnd a series of corrected transmittance values {TC₁₂}_iUsed to find out. T_12c= F₁₂(C_12c). These values are the transmittance necessary to obtain a constant R ratio.
4). Input transmittance {T₁₂}_iAnd corrected transmittance {T_12c}_iSeries of differences {ΔT_12c}_iCreate In this case ΔT₁₂= (T_12C-T₁₂) / T₁₂It is.
5. {ΔT₁₂}_iAnd {C₁₃}_iAnd the optimal polynomial polynomial ΔT having an order of 3 to 5 depending on the number of concentrations used as input data₁₂= P (C₁₃).
6). Current C₁₃And C₁₂Is used to determine new deltas and new concentrations for the corrected input transmission, and the correlation between these new concentrations and the new delta.
7). New P (C₁₃) Use the correction polynomial to replace the old polynomial with the new one when the correlation between the new density and the new delta is reduced.
[0106]
If the soft calibration procedure is successful, the result appears as a lower value correlation between delta and concentration. Since soft calibration is performed continuously and each new negative data set obtained is added to the database, the calibration cycle needs to be repeated more than a single cycle. As long as the correlation is reduced, the use of a new correction polynomial ensures that the soft calibration performs the correction operation and that the correlation error converges continuously.
[0107]
4). Input capnograph calibration
In addition to the calibration test described above for the accuracy of overall instrument operation, according to another preferred embodiment of the present invention, a specific test for the calibration of the capnograph probe upon entry to the instrument is also performed. Since the capnograph probe measures the waveform of the input breath, it can accurately define the portion of the waveform to be collected or rejected. Since the capnograph does not have the same level of measurement accuracy as the breath tester, a procedure that uses the results of a high-precision breath test measurement is used to calibrate the input capnograph.
[0108]
CO installed at the system entrance₂Capnograph probe is CO₂Allows concentration measurement. Preferably, the content concentration of the accumulated sample at the end of the filling process is estimated by integrating the capnographic measured concentration of all exhaled waveform portions collected by the intermediate chamber system. The accuracy of such measurements is related to the shape of the capnograph absorption curve that may have changed based on operating conditions. This accumulated sample content concentration is now measured in the gas analyzer sample chamber. In the gas analyzer sample chamber, the concentration is measured with high accuracy. This concentration is then₂By correcting the probe calibration, the estimated bag concentration is equal to the measured concentration because it is used to correct the capnograph absorption curve in response to the current environmental conditions present in the system.
[0109]
Patient preparation and testing procedures
1. Patient preparation
Prior to applying a breath test, it is wise and customary for doctors to pay attention to details about any medications they have taken that may interfere with the test results when listening to the patient's medical history . Specifically, patients are typically asked as to whether they have recently taken antibiotics or other therapeutic agents according to conventional methods. This is because such drugs can affect the results of a breath test depending on what the particular breath test is being performed. The breath test methods described in some of the prior art use two measurement points based on a single bag of breath sample collected before substrate intake and a single bag after substrate intake, or As a best practice, use three measurement points based on one sample bag before substrate intake and two sample bags collected at different times after substrate intake. When using these methods, weeks to stop breathing after taking antibiotics or certain other gastrointestinal treatments to avoid the risk of false negative results It is recommended to have a time interval. For example, the breath test includes an operational recommendation given by Alimenterics Inc., New Jersey Morris Plains, a manufacturer of LARA (Laser Assisted Ratio Analyzer) for detecting Helicobacter pylori in the upper gastrointestinal tract. It has been suggested that if you take antibacterial drugs, omeprazole (proton pump inhibitor) and bismuth preparations within 4 weeks prior to the treatment, false negative results may occur.
[0110]
The reason for this recommended period of drug discontinuation is the physiological dynamics in which isotope-labeled components appear in the exhaled breath of the patient, because bacterial suppression causes a mechanism that increases the isotope ratio. The drug can be significantly affected. According to such conventional methods, this method can lead to false diagnostic results, specifically false negative results due to reduced response levels or delayed dynamics of physiological responses. This makes it necessary to question the reliability of breath tests performed within a specific period of such medication.
[0111]
In accordance with a preferred embodiment of the method of the present invention, utilizing multiple samples online and monitoring the isotope ratio in exhaled breath as described herein is substantially continuous Unlike conventional methods that measure up to two discrete samples following ingestion of labeled substrate, it makes it easier to detect most changes in patient response. Thus, unlike conventional methods, the preferred method of the present invention also provides that the patient is currently receiving PPI therapy for the treatment of stomach upset or H. pylori also receives antibiotics and other treatments to eradicate the invasion of H. pylori. A breath test for H. pylori can be performed with an acceptable rate of specificity and sensitivity. In the worst case, doctors can use the knowledge that the patient was receiving such therapy in the period just before the test and assign a slightly lower “confidence level” parameter to the result, in which case its significance There is no need to change substantially.
[0112]
Furthermore, according to many of the recommended procedures following conventional breath tests, patients typically fast for several hours before the breath test to eliminate the effects of changes in isotope ratios that result from specific food intake. Advised to do. For example, corn-rich foods have a higher baseline than others¹³CO₂Results in an isotope ratio. According to the present invention, it is desirable that the patient need not fast before the test because the time required to perform the breath test is short. This is because any change in the isotope ratio resulting from a particular food intake is This is because it typically occurs at a much slower rate than the changes measured in the breath test due to H. pylori activity. This advantage is enhanced by the fact that it is possible with the present invention to monitor changes in isotope ratios that are measured virtually continuously. The above advantages are therefore opposed to the effect that the dynamic response to urea can occur in different situations due to uncertainty about the patient's time since the latest food intake. Furthermore, food intake results in covering the inner wall of the stomach, which causes H.P. There is testimony pointing out the fact that pylori activity is reduced. Even in such a situation, in the case of the present invention, the change in the isotope ratio can be monitored virtually continuously, so that it is possible to detect a more difficult change in the isotope ratio. A higher level of measurement reliability is provided than other methods.
[0113]
Reference is made to FIGS. 4A-4E which illustrate the situation typically occurring during a breath test. For this situation, conventional discontinuous breath sample collection methods and analyses have made false diagnoses that give false positive or negative results. These cases can be correctly diagnosed by using a virtually continuous sampling method and analysis according to the preferred embodiment of the present invention.
[0114]
In FIG. 4A a very slowly but monotonically increasing isotope ratio plot is shown. This type of response can occur, for example, when a test is performed on a subject too soon after food intake. When the labeled substrate is absorbed from a full stomach, the absorption rate is considerably slower than in other cases. There is also significant dilution from other contents of the stomach. Thus, even if the subject is unmistakably positive, the resulting isotope ratio may exhibit a gradual increase. The same effect is seen in subjects with low gastric absorption levels or subjects receiving medication for treatment or eradication of the disease or bacteria being examined.
[0115]
According to the conventional method of collecting a single or a maximum of two sample bags after a predetermined time since the ingestion of the labeled substrate, these time points t₁, T₂, The isotope ratio has not reached the upper threshold level T / H. If this upper threshold level is crossed, it is determined that a positive result is indicated. As is apparent from the figure, t₂Even after a significant amount of time has passed, the threshold levels may barely cross, or, according to all commonly accepted records, may not cross at all for a long time after the expiration of the breath test. Therefore, this subject was determined to be negative.
[0116]
However, according to the preferred method of the present invention, the breath tester can effectively collect and monitor multiple breath samples, allowing the breath tester analysis software to detect continuous increases in isotope ratio. Thus, such a subject is diagnosed more accurately as being positive. Therefore, using such a method makes it possible to perform a more reliable breath test. In addition, the method is preferably more reliable for subjects undergoing fasting prior to testing, and also on subjects undergoing drug therapy for treatment or eradication of the clinical condition or bacteria being tested. Allows breath tests to be performed. In addition, the method preferably enables faster results compared to the conventional discontinuous sample bag method.
[0117]
Reference is made to FIG. 4B which shows an example plot of a subject's breath test. This condition of the subject results in an unstable level of metabolic substrate and thus an unstable level of isotope ratio of exhaled breath from the subject. However, the subject does not show the clinical symptoms of the condition sought in the breath test. According to some conventional methods, the sample bag is accidentally₁If collected for analysis, the subject will be diagnosed as positive. However, using the preferred method according to the present invention gives correct negative results. This is because no clear upward trend is detected.
[0118]
In the situation shown in FIG. 4C, referenced next, the isotope ratio rises significantly and exceeds the threshold T / H, but then reaches a steady flat level just above the threshold. Such a physiological result is the point t₁According to the conventional single point test carried out in (1), it is determined as positive, but according to the analysis method used in the present invention, it is correctly interpreted as negative.
[0119]
Lastly referenced FIG. 4D shows a plot 450 of breath test results. The result is the time t₁First of all, it is interpreted as giving a positive result, whether by the conventional discontinuous bag collection method in, or by the method of the present invention using a virtually continuous collection and analysis of isotope ratios. Will be. On the other hand, the value 452 of the carbon dioxide concentration of the sample measured at each time point on the graph is plotted on the same graph. It is observed that the concentration shows a strong correlation with the ratio measured at each time point.
[0120]
According to the preferred method of the present invention, the correlation between concentration and isotope ratio results from an incorrect calibration condition of the gas analyzer, possibly as a result of a shift in one of the absorption curves. It will be detected by one of the self-diagnostic routines performed within the device. A patient calibration procedure is then performed to correct the parameters of the absorption curve, thereby reducing the found correlation and using the original data with the newly calculated absorption curve, Is recalculated retroactively. FIG. 4E shows the result of this recalculation procedure performed after calibration. As can be seen, the isotope ratio is now low and wavy, indicating that the test results are actually negative.
[0121]
2. Substrate preparation and administration
According to a further preferred embodiment of the invention, a procedure for the administration of the labeled substrate is practiced. In this regard, H.C. The method used in the breath test for detecting H. pylori will be described. In this test, urea is used as an isotope-labeled substrate. For the current situation of practicing this procedure, a number of recently issued patent applications such as WO 98/21579 (WO 98/21579), titled “Detecting Helicobacter pylori” by A. Becerro de Bengoa Vallejo Method and kit for detecting Helicobacter pylori "and WO 96/14091 by C. Nystrom et al., Entitled" Diagnostic preparation of detection ". of Helicobacter pylori) ”. The above pamphlets are incorporated herein by reference in their entirety for reference.
[0122]
As efficiently as possible. In order to detect the activity of H. pylori, It is well known to those skilled in the art that the pH value of the pyloric sinus should be maintained at the natural acidic level, which is an environment in which H. pylori persists without hindering its urease activity, as in the above-mentioned de Bengoa Vallejo international application. Are known. This is achieved by giving the patient about 200 ml of a drink consisting of water-soluble citric acid, pH 2-2.5, instead of the water used for the earliest breath test, prior to administration of urea. Is preferred. D.Y. Graham et al., Published in The American Journal of Gastroenterology (Vol. 94, 1214-1217, May 1999).¹³A paper entitled "Citric Acid as the Test Meal for the 13C-Urea Breath Test" was performed on patients after ingesting a citric acid solution. The results of the breath test are listed. Using 4 g of citric acid resulted in significantly faster positive patient results than using only 1 g of citric acid or only water. The use of citric acid has three additional well-known advantages. First, citric acid delays gastric emptying, thereby maintaining a full amount of urea in the stomach for an extended period of time, and second, H.P. Ongoing P. pylori as given to a large number of applicants for H. pylori detection breath tests. P. Helps to block the effects of I therapy, and third, citrate reduces the activity of oral bacteria known to cause interference with breath tests.
[0123]
Therefore, this well-known procedure is to give the patient about 200 ml of diluted citrate drink before or with the administration of urea. Since the stability of urea in solution is not always guaranteed over time, a generally accepted procedure is to provide powdered or tableted urea, which is then dissolved in water or as a drink Given.
[0124]
According to a preferred embodiment of the method of the invention, urea is provided in the form of a tablet, which is dissolved directly in a citric acid solution and then drunk or taken by a straw. The use of a straw ensures that urea has minimal contact with the oral cavity, which reduces the effects of oral bacteria. Such a procedure has many advantages. First, tablets can be packaged and used more simply than powder. Secondly, when used as a tablet, it becomes clear that all of the urea has dissolved, so the entire dose is immediately active upon ingestion. Third, depending on the tablet structure, urea dissolves more easily in citric acid solution than in water. For example, a tablet consisting of 50% urea and 50% sodium chloride, with a silicate binder and cellulosic agent, takes almost half of the time it takes to dissolve in water, ie in about 4 minutes versus nearly 8 minutes. Dissolve completely in citric acid solution.
[0125]
Kit identification
The breath tester device according to the preferred embodiment of the present invention can be used for many different tests. Some of these tests are described in the “Background” section of this application, and are further described in the pamphlet of WO 99/12471 (WO99 / 12471) mentioned in the Background section. Each test uses a unique kit consisting of an isotope-labeled substrate and possible accessory solution components, such as urea and citric acid used in breath tests to diagnose Helicobacter pylori in the upper gastrointestinal tract . Each test procedure may also have its own test protocol with respect to elapsed time and level of detection for the gas being detected, so that the correct kit is used for the selected breath test and vice versa. It is important that a means for assuring is provided. Furthermore, the amount of substrate and associated solvent used can be prepared depending on the patient's age, weight, medical history or race or place of birth. In addition, breath test parameters are adjusted accordingly. Finally, some pharmacological lifetimes of the active substances in the kit may be constrained, so if you try to use an expired kit, warn the user or make the instrument inoperable This is very important.
[0126]
In accordance with another preferred embodiment of the present invention, each individual breath test substance is supplied in a kit with a disposable oral / nasal cannula or other breath delivery tube used to perform the test. The No. 08/961013, entitled `` Fluid Analyzer with Tube Connector Verifier '' by several of the inventors of the present invention pending with the present invention The tube connection verifier disclosed in is operable to ensure that the correct tube is being used for a test performed by the analytical instrument and that the connector is correctly installed. The above specification is incorporated herein for reference. According to this embodiment of the invention, the connector of the oral / nasal cannula or the like can be encoded with an identification code. The identification code includes information about which material is included in the kit with the cannula, the amount of the material, and its expiration date. Means are provided on the connector of the breath tester device for reading the information supplied when the oral / nasal cannula or the like is connected to the device. This means may comprise optical, electronic, magnetic or mechanical means, including for example bar code scanning means, digital pulses or similarly effective means. Communication automatically enters data into the instrument automatically when the cannula or equivalent connector is plugged into the breath tester, or when the operator keys the details of the examination into the instrument Can be operated in query mode.
[0127]
Alternatively and preferably, a tracer or marker substance is added in the breath test kit. Means for detecting this marker are provided in the instrument. According to this preferred embodiment, even if the cannula is not utilized with the encoded substance information as provided in the kit, the contents, amount and expiration date of the breath test substance are both determined by the breath test equipment. Can be identified.
[0128]
According to another preferred embodiment of the present invention, a marker added to the substrate in the breath test kit can be used to initiate analysis of the collected breath. According to this example, a substance such as labeled glucose is added to the substrate. This substance is absorbed very rapidly by the stomach into the bloodstream, and immediately afterwards, its metabolic byproducts appear in the exhaled breath of the subject. When the marker marker by-product from glucose is detected by the instrument, this means that the substrate has been ingested, its absorption in the stomach has begun, and that the substrate is fully compatible with the physiological effect being investigated. It is a signal of progressing through metabolic pathways. However, this marker marker by-product has immunity to the specific disease, bacteria, or physiological dysfunction being sought and appears regardless of the presence of the disease or dysfunction. Such a signal is used to command the instrument control system to begin analyzing the collected breath sample for specific by-products of the test being performed. This method is particularly advantageous when used in conjunction with an extended breath test. This is because the marker provides a signal as to when the onset of substrate by-products can be expected.
[0129]
According to another preferred embodiment of the present invention, a gas can be incorporated into the substrate instead of a solid such as glucose. The gas is released upon dissolution of the substrate in the gastric fluid and is detected directly in the breath. In this case, it is not necessary to implement a complete circuit consisting of absorption, metabolism and lung exhalation. As another example, the gas can be produced from a parent material that generates a marker gas upon contact with gastric acid.
[0130]
In all of these examples employing marker substances, whether incorporating gas or producing direct or indirect gaseous by-products, the gas is the same as the gas to be detected in a particular breath test. In this case, it is important that the influence of the marker gas is short-term so as not to prevent detection of the true by-product of the breath test.
[0131]
Analysis of breath test results
By the method disclosed in the above-mentioned WO99 / 12471 (WO99 / 12471) pamphlet, titled “Breath Test Analyzer” by several of the inventors of the present application, It ends when it is determined by the result of the inspection itself. This is similar to the method disclosed above. This allows the instrument to determine that clinically significant conclusions have been obtained according to the current test results, thereby allowing the instrument to determine that the breath sample has been collected virtually continuously. As most of the prior art is, the conclusion of the test can be obtained sooner than by the sampling method using a single or two non-consecutive sampling points. According to another embodiment of the present invention, the breath test apparatus comprises a signal means for instructing the operator that a clinically significant result has been obtained and that the test may be terminated. Alternatively and preferably, the signal may be visible by one or more indicator lights, or may be audible by tone or by a suitable real-time indicating method or indicating device. FIG. 13 of the PCT application issued as the above-mentioned International Publication No. 00/74553 (WO00 / 74553) pamphlet shows a signal to the operator that a significant result has been obtained on the front panel of the breath test apparatus 210. Two alternative embodiments for notification are shown. One of these is shown in the form of an indicator lamp 231 and the other in the form of a loudspeaker 233. The pamphlet is cited in this specification for reference. According to another embodiment of the invention, different signals, for example different color light outputs or different tones, indicate whether the test conclusion is positive or negative in order to indicate different conclusions of the test. May be used for
[0132]
In accordance with another preferred embodiment of the present invention, a number of methods are provided for calculating gas analysis results. Thereby, the judgment regarding the breath test result can be obtained earlier or more reliably than the conventional method.
[0133]
(A) Identifying oral activity
According to a preferred embodiment of the present invention, one of the benefits of virtually continuous sample analysis is the effect of oral bacterial activity resulting from direct effects on bacterial substrates in the oral, nasal or pharyngeal passages. It is possible to distinguish from the true stomach effects. As is the case with most conventional methods, when measuring at only one or up to two points after ingestion of a substrate, high isotope CO₂Isotope CO ratio derived from stomach interaction₂Whether it is based on an increase in the ratio or isotope CO₂It can be difficult to reliably determine whether the ratio drop is from the final stage of oral activity. This is a false positive result rate.
[0134]
Preferably, a calculation method is used that effectively and continuously monitors the isotope ratio according to the present invention and determines whether the isotope ratio is rising or falling. Distinguish between positive results and decline in oral activity. Since the method involves plotting the results from the start of the test, the characteristic rise and fall of oral activity are detected completely clearly. According to a preferred embodiment of the present invention, the characteristic peak of DoB is reduced to a low threshold within a time that is clearly shorter than the time taken to detect the effect of the true physiological effect sought in the breath test. If a rising and falling value is detected that exceeds and returns to the low threshold, the response is considered a result from oral activity and is therefore ignored. H. During a breath test for H. pylori, the typical time frame for completion of any oral activity is on the order of 8 minutes from the ingestion of the labeled substrate. Typical values for the oral activity peak are all about a rise of about 10 &dgr; that occurs within a period of 4 to 8 minutes from the ingestion of urea, with the concomitant drop of 5 &dgr;
[0135]
It should be noted that when the term “oral activity” is used and claimed herein, the term includes physiological side effects that increase the isotope ratio in exhaled breath from the subject. This side effect is independent of the effect sought by the breath test, or occurs independently of the metabolic pathway associated with the physiological condition under investigation.
[0136]
(B) Change in isotope ratio
Carbon dioxide isotope ratio in exhaled breath exhaled from the subject¹³CO₂/¹²CO₂In order to determine the increase, generally accepted methods measure the baseline level of background isotope ratio in the subject's breath prior to administration of the substrate. This partial increase in isotope ratio above the baseline is expressed in terms of the well-known “delta over baseline” parameter. In commonly used conventional methods, DoB is commonly expressed as a scaling parameter, delta δ or, more precisely, thousandths of delta. In this normalization parameter, the isotope ratio R of sample 1₁And the isotope ratio R of the reference sample R_RThe delta between is defined as follows:
δ₁  = 1000 * (R₁-R_R) / R_R
[0137]
The reference sample traditionally used is a standard geological rock known as Pee Dee Belemnite limestone. Therefore, the reference isotope ratio R_pdbIs the carbon isotope ratio found in naturally occurring PDB limestone¹³CO /¹²It is CO and has a value of 1.11273%.
[0138]
The delta over baseline between measurement 1 and measurement 2 is given as follows:
DoB = δ₁−δ₂,in this case,
δ₁= 1000 * (R₁-R_pdb) / R_pdb
δ₂= 1000 * (R₂-R_pdb) / R_pdb
[0139]
Therefore, DoB = 1000 * (R₁-R₂) / R_pdb,in this case:
R₁Is the isotope ratio measured in sample 1 at time point 1;
R₂Is the isotope ratio measured on sample 2 at time 1.
[0140]
For normal subjects, the isotopic ratio of the baseline breath sample is essentially the isotope of carbon dioxide resulting from the metabolism of organic compounds derived from plant or animal food consumed by the subject. Body ratio. Since such nutrients generally have isotope carbon ratios that are significantly lower than the typical isotope carbon ratio of naturally occurring carbon dioxide in air and lower than the isotope carbon ratio of PDB, The baseline isotope ratio of exhaled breath from a normal subject is usually R by an amount in the range of slightly above 15δ to about 27δ depending on the subject._pdbIs significantly smaller than. Thus, DoB, according to commonly used definitions, is expressed as a partial difference in isotope ratio between two measurements for a specific fixed ratio that is generally slightly elevated from the typical baseline ratio. The
[0141]
According to another preferred embodiment of the present invention, in some cases, a partial difference in the isotope ratio between two measurements for a particular fixed ratio is obtained without requiring a baseline measurement. It is possible to use. According to this preferred embodiment, the measurement of changes in isotope ratio is performed with sufficient sensitivity so that measurements taken following substrate uptake can be obtained without knowing the baseline level. It is sufficient to detect the desired change. It is important to note that when using the various parameters for calculating changes in isotope ratios described throughout this section and throughout this disclosure, the term "delta over baseline" It should be interpreted broadly to mean a delta difference above the previously measured value and not strictly adhere to baseline level perception.
[0142]
Regardless of what means is used, while measuring the isotope ratio in the breath sample, the measurement conditions in the sample cell and reference cell may vary from correctly calibrated conditions. Several types of breath tests, such as assessment of fat malabsorption, gastric emptying rate or liver function tests, are performed over a considerable period of time and can be as long as several hours. In such a case, even if there is a slight drift in the instrument during that time, this becomes extremely serious. Thus, if a systematic error in the ratio measurement occurs, for example due to inaccurate calibration resulting from a shift in the gas absorption curve, it is calculated even if the measurement error of the two ratio changes approximated to each other is very small. DoB values will include complete systematic errors. This is because each ratio having a value that may be quite different from the currently measured ratio is a fixed value R_pdbIt is because it is normalized with respect to.
[0143]
In order to avoid such drawbacks, δ 'defined instead is proposed in WO97 / 14029 (WO97 / 14029) pamphlet filed with PCT by Otsuka Pharmaceutical Co. In this case, with respect to the ratio R between samples 0 and 1:
δ ’₁  = 1000 * (R₁-R₀) / R₀
It is.
Such a definition of δ 'is R_pdbInstead of R₀With the denominator. R₀In other words, the baseline ratio and R₁That is, the difference from the next measurement point is the above-mentioned R₀And R_pdbIs generally much smaller than the difference between Therefore, the value of δ 'is less sensitive to changes in measurement conditions resulting from the shift of the absorption curve than the value of δ. Because δ 'is the ratio R being measured.₁Ratio R approximating to₀Has been standardized against. There are conventional measurement methods that attempt to overcome the problem of having to compensate for drift in the absorption curve by using such δ '.
[0144]
On the other side, the value of δ 'is R₀The absolute result is related to the baseline of the particular subject being measured, and thus the subject's eating habits, or the time elapsed since the last meal, or baseline May vary depending on factors such as hometown known to influence the level. Baseline level differences between different subjects may range from about 10δ as described above. For this reason, R₀Using the δ 'associated with, it is not possible to make absolute numerical comparisons between results obtained from different subjects.
[0145]
Table 1 below refers to R in the second column.₀A number of calculated values of DoB normalized to_pdbCompared to a traditional DoB standardized. The first column is the true isotope ratio measured by mass spectrometry. The parameter RCIR will be described later. As is apparent from the table, as the sample isotope ratio increases, R₀DoB normalized to is R_pdbDeviate from the traditional DoB value normalized to. Deviation levels expressed with very high isotope ratios are typical for specific studies, statistical studies that require comparison of test results for different subjects, and baseline ratios can vary significantly When comparing subjects taken at time intervals of several weeks, the difference between DoB parameters is relevant, although it has little clinical significance. And therefore R_pdbThe classic DoB called is preferably used.
Table-1

[0146]
In order to overcome the relevance of the breath test results measured with respect to changes in the absorption curve, according to a preferred embodiment of the present invention, the breath test device can perform various compensation procedures such as soft calibration, self-calibration as described above. Alternatively, each procedure for patient calibration may be incorporated. When one such calibration procedure is performed, for example, a sample of the patient's breath that does not show a significant change in the isotope ratio (“negative” patient) is used in the calibration method and the isotope ratio of the breath is determined as R_pdbCan be approximated by The parameters of the absorption curve were adjusted by an iterative calibration procedure and, as expected, the measured ratio was R_pdbIs actually found to be a ratio of True ratio is 20δ or R_pdbEven if we know that it is below the value of_pdbUsing the estimated approximation for し か has only a small effect on the measured DoB value. Thus, for example, the true ratio of the above-mentioned negative patient sample is the estimated R_pdb= 1.11273%, but in fact R = 1.07% (a typical value for negative patients)_pdbThe measured DoB error resulting from the use of the approximate value is only 3% of the measured value. This means that a reading of 5.15δ is obtained rather than 5δ, and such deviation is not significant at all. The relevance of the measured DoB absolute value to the subject's baseline level is minimal.
[0147]
Unusually high baseline ratio, R_pdbIn the other extreme example of a subject who has even a baseline ratio as high as 60 δ above the estimated value, the use of the iterative calibration method will affect the resulting DoB measurement below 1 δ. Since the spread of the baseline isotope ratio between different subjects is typically well below this value of 60 δ, the use of the preferred calibration method of the present invention as described above provides accurate breath test results. Make it possible. Such a result can be attributed to generally accepted DoB parameters and is independent of the actual baseline of the patient being examined.
[0148]
R used in the above calibration_pdb Even if the deviation in the DoB measurement caused by the approximation is small, this deviation is preferably compensated by measuring the ratio for a sample with a known isotope ratio, for example by performing a calibration check of the instrument. can do. According to another preferred embodiment of the present invention, the above definition of δ 'is used with another parameter known as "relative change in the isotopic ratio" or RCIR. The parameter RCIR is preferably used in place of conventional DoB to ascertain an increase in the exhaled breath isotope ratio. RCIR is defined by the following expression:
RCIR_n= RCIR_n-1  + 1000 * (R_n-R_n-1) / R_n-1
In this case R_nCorresponds to the measured value n¹³CO₂/¹²CO₂Isotope ratio. By definition, for baseline measurements, RCIR₀= 0.
[0149]
According to the above definition of RCIR, the normalization is the previous measurement point R_n-1Is preferably carried out. Another preferred definition can be used for RCIR:
RCIR_n(+) = RCIR_n-1  + 1000 * (R_n-R_n-1) / R_n
In this case, normalization is performed with respect to the ratio at the current measurement point. Positive result R_n> R_n-1RCIR during the course of a breath test showing_nThe result achieved using (+) is the previously defined RCIR_nThan the results obtained using_pdbApproximate the result obtained for.
[0150]
According to another preferred embodiment of the present invention, these two types of normalization for RCIR calculate the results of each measurement depending on whether the measured isotope ratio is increasing or decreasing. Used alternately. If the isotope ratio is increasing, ie R_n-1<R_nIn this case, the second definition RCIR (+) is used. If the isotope ratio is falling, that is R_n<R_n-1The first definition RCIR_nIs used. This calculation method using alternating RCIR parameters, whether the ratio curve turns from increasing to decreasing or vice versa, or whether it originates from an instrumental source or a physiological source, It is advantageous to smooth the slope of the result when there is a high level of noise at the measurement point. This method is also advantageous for compensating measurement points that deviate particularly from the overall tendency of the plotted curve.
[0151]
A further advantage of using RCIR parameters that are alternately defined according to the trend of the measured isotope ratio is in the accuracy of the results obtained. Using the RCIR parameter as a single definition, depending on the direction of the change, the change in the ratio is enhanced or the change in the ratio is not stressed. Thus, for example, the previous reading R_n-1First RCIR scaled against_nUsing the parameter exaggerates the increasing ratio. That's because of the growing RIR of the RCIR denominator_n-1Is R_nBecause it is smaller than. Similarly, RCIR_nUsing will obviously reduce the rate of decrease of the descending ratio. That's because the denominator R_n-1Is the current ratio R_nIt is because it is larger than. RCIR_nUsing the (+) parameter has the opposite effect: the increase is not stressed and the decrease is exaggerated.
[0152]
As a result, if one or the other of the RCIR parameters is used in the analysis of the breath test performed, the wavy ratio curve is an accumulation of ratio errors. In contrast, according to a preferred embodiment of the present invention that uses alternating RCIR parameters depending on the trend of the measured value, the wavy curve always reflects the true measurement result, so that, for example, the ratio is its original Returning to the value will always return the curve to its original level.
[0153]
The instrument drift that occurs during the measurement process is significantly different from the effect on the conventional DoB and does not affect the parameter RCIR. The last column of Table 1 above shows RCIR parameter values calculated for each given isotope value. As is apparent from this, the RCIR value follows the classic DoB value with a high DoB value and a small deviation.
[0154]
In accordance with another preferred embodiment of the present invention, RCIR is a measurement that greatly overcomes the major problems in performing breath tests over a relatively long period of time, such as the test described above, which is well over one hour. Can be used in the law. In such a situation, for example, due to a change in the absorption curve accompanying a change in environmental conditions, specifically, a change in temperature, a lot of drafts are generated in the device. In this situation, if a baseline reference is taken near the beginning of the test, there is no easy way to accurately compare this baseline measurement with the isotope ratio obtained quite later during the test. This is because the measurement conditions may generally change. The comparison is therefore not valid.
[0155]
In addition, optical spectroscopic gas analysis methods, including some used in breath tests, require the sample to have the same major isotope component concentration as the baseline sample, so the light transmission measured in the sample cell. The rate (absorption rate) can be directly related to the concentration of the component gas in the sample cell. The concentration can be made equal by diluting each collected sample to a predetermined concentration with an inert gas. The concentration is typically chosen to be the lower limit of the normal range of achieved concentrations to be examined, so the majority of the actual collected sample is diluted to the same predetermined concentration value. can do.
[0156]
The above-mentioned WO 97/14029 (WO97 / 14029) pamphlet filed PCT by Otsuka Pharmaceutical Co. compares the concentration of two sample bags in order to equalize the concentration between the two samples. Describes a method of diluting a higher sample to a lower concentration. Unfortunately, the lowest concentration for a large number of samples, each collected in a different sample bag, or for an on-line measurement that efficiently and semi-continuously monitors the expiration of the sample as described in the present invention. It is not practical to apply the dilution method. Comparing large sample sets requires complex systems that handle and temporarily store samples. This is because each sample needs to be finally compared with every other sample.
[0157]
In addition, since the stable measurement conditions cannot generally be maintained during a typical breath test, Otsuka's method provides a ratio R related to the change in the isotope ratio of the sample.₀Is used and this ratio R₀Another disadvantage arises because may be separated from the measured sample ratio. Similarly, when comparing the n th sample with the n−1 th sample, the ratio R_n-1If is used for scaling, the resulting trend is extremely exaggerated and any change is over-emphasized.
[0158]
In accordance with the preferred embodiment described in the present invention, the disadvantages described above in Otsuka's method, which makes it possible to bring individual sample pairs n-1 and n to the same concentration by utilizing alternating PCIR parameters, Resolved without reference to the sample pair. Thereafter, the n + 1 th sample is measured in relation to the new measurement of the n th sample.
[0159]
Another method commonly used for conventional carbon dioxide breath testing to achieve correct sample dilution is:¹²CO₂This is done by comparing the IR transmission with a reference sample of known concentration. For the reasons described above, the ability to equalize samples is the same issue of instrument stability that affects the absorption measurement itself, as comparative absorption measurements can be inaccurate when performed at significantly different times. Also affected by. Therefore, according to the method used in this regard, when samples are collected and measured at significantly different times, the accuracy of the breath test is in the ability to perform an accurate comparative absorption measurement with reference to the baseline sample. Related in two distinct ways. That is, the first is the ability to accurately dilute the sample to the same concentration, and the second is the ability to accurately perform the actual absorption measurement.
[0160]
There are many ways to overcome this problem. One method is to collect a very large amount of baseline sample and divide it into separate parts. These separate parts are used to compare each subsequent sample collected as the test progresses with a portion of the original baseline sample under the conditions under which this subsequent sample is measured. It will be enough. This makes the comparison more accurate. Alternatively, a separate sample of baseline samples may be drawn for each successive breath comparison. These methods are cumbersome to implement and generally not easily implemented due to the practical problem of collecting a large initial baseline sample that is sufficient after splitting for each comparative measurement. .
[0161]
In another simpler procedure proposed in US Pat. No. 5,146,294 issued to R. Grisar et al., A storage container is used to supply a continuous sample of reference gas. The reference gas is transferred into the measurement chamber between each measurement of the diluted breath sample under conditions that are as identical as possible to the diluted sample breath. The accuracy of such a method appears to be limited by the accuracy with which the system can be temperature stabilized and the accuracy with which the reference sample can be repeatedly measured under the same pressure conditions.
[0162]
According to another preferred embodiment of the present invention, a single initial baseline sample consisting of exhaled breath is collected in a different standard measurement method than that described above, and each sample collected during the examination. Repeatedly measure the same baseline sample immediately before and / or immediately after each sample collected during inspection by loading / unloading the baseline sample to / from the measurement cell between each measurement To do. The baseline sample is thus measured under conditions similar to those of the collected sample. To implement this method, an accurate gas handling system is required to avoid contamination of a single baseline sample due to loss, leakage, or dilution.
[0163]
Alternatively and preferably, and more simply, such a single baseline sample may be stored in its own reference cell and compared to the sample gas in the measurement cell for each measurement of a newly collected sample. Good. Such means have the disadvantage that the measurement path has to be switched between different cells in order to carry out the respective measurements.
[0164]
A calibration method for performing all of the above procedures is preferably established using different definitions for the change in isotope ratio from a fixed point relative to an absolute or variable ratio. In this case, the isotope deviation of the measurement ratio is given by any of the following expressions, depending on which reference ratio is used.
(A) (R_n-R_{0 (n)}* 1000 / R_{0 (n)}  Or
(B) (R_n-R_{0 (n)}* 1000 / R_pdb
In this case R_nAnd R_{0 (n)}Are the measured isotope ratio and baseline reference measured at the nth measurement point, respectively.
[0165]
For example, due to excessive equipment drift, R_pdbIf an absolute normalized measurement such as that performed for can not be achieved, the relative isotope deviation may take the following form:
(C) (R_n-R_{0 (n)}* 1000 / R_n
R_n≧ R_{0 (n)}Thus, the expression (c) is closer to the expression (b) related to the standard PDB than to (a).
[0166]
If the reference ratio is not a baseline measurement, the change in isotope ratio from this point is preferably calculated with respect to the previous result. Thus, depending on the definition used, the deviation is obtained by subtracting one of the following terms from the previous result:
(D) (R_n-R_{ref (n)}* 1000 / R_{ref (n)}  Or
(E) (R_n-R_{ref (n)}* 1000 / R_pdb
In this case, R_nAnd R_{ref (n)}Are the measurement ratio itself and the reference ratio measured at the nth measurement point, respectively.
[0167]
For example, due to excessive equipment drift, R_pdbIf absolute normalized measurements such as those made for can not be achieved, the relative isotope deviation preferably takes the following form:
(F) (R_n-R_{ref (n)}* 1000 / R_n
R_n≧ R_{0 (n)}Thus, the expression (f) is closer to the expression (e) associated with the standard PDB than to (d).
[0168]
With respect to the first point (baseline), the relative change in isotope ratio can be expressed as:
(R₀-R_{ref (0)}* 1000 / R_{ref (0), pdb Or 0}
In contrast, for the nth measurement point, if the measurement is performed with respect to the baseline:
(R_n-R_{ref (n)}* 1000 / R_{ref (n), pdb Or n} -(R₀-R_{ref (0)}* 1000 / R_{ref (0), pdb Or 0}
Or, when the RCIR calculation method is used,
(R_n-R_{ref (n)}* 1000 / R_{ref (n), pdb Or n} -(R_n-1-R_{ref (n-1)}* 1000 / R_{ref (n-1), pdb Or n-1}
[0169]
According to another preferred embodiment of the present invention, a method using RCIR parameters is proposed. The RCIR parameter broadly overcomes the above-mentioned problems associated with comparing a collected sample with a single baseline sample during a long breath test. According to this preferred method, a sample pair is collected for each measurement point except for the first measurement point. At the first measurement point, only one sample is required to collect, which is generally a baseline sample. At any successive measurement point n, one of the collected sample pairs is taken from the measurement point (n-1), typically the sample pair from the previous measurement point for a relatively short time. Compared with one of the samples, the other sample of the sample pair is stored for comparison with one sample of the sample pair to be collected at the next measurement point (n + 1) Is done. At the last measurement point, two samples are collected, but only one is necessary for the measurement. This is because the inspection ends at this point.
[0170]
The method of this example has been described in terms of “collecting” two separate samples at each measurement point, but in practice it is not necessary to physically collect two separate samples. For example, a single sample is collected and used in half at each of the two relevant measurement points, or a single sample is collected and measured once at each measurement point, twice in total. It is possible or other suitable variations of this method are conceivable.
[0171]
The time between each measurement point is relatively short compared to the total elapsed time of a complete breath test and ranges from significantly less than 1 minute to more than 30 minutes, depending on the type of test being performed. Is typically occupied. Therefore, more maintaining the integrity of the sample and the stability of the measurement conditions over a relatively short time between one measurement point and the next measurement point will maintain this from the start to the end of the breath test. It is simple compared to
[0172]
In this way, a reference movable frame is generated, which is compared with the previous measurement point under the measurement conditions that can occur most closely, and how the measurement conditions change temporarily due to instrument drift. Regardless of whether or not, each measurement point can be referred back to the previous measurement point.
[0173]
The computer procedure for comparing sample pairs according to a preferred embodiment of the present invention can be understood with reference to FIG. FIG. 5 shows that the measured isotope ratio R can change as a function of elapsed time due to instrument drift, such as that resulting from changes in absorption curves. The illustrated graph is only for illustrative purposes. This plot shows the ratio change actually measured by the instrument versus the ideal fixed ratio as if the breath test gave a negative result with no change in the true isotope ratio. Yes. A similar explanation is possible for situations that are more likely to occur when the ratio is actually changing, but for simplicity this embodiment will be described using a fixed ratio.
[0174]
Change in isotope ratio at time t₀Using the conventional method of comparing with baseline reference measurements at₁The change in the isotope ratio measured by₁It becomes. Time t₂At the next measurement point provided at, the measured change in isotope ratio is caused by ΔR as a result of instrument drift.₂Will be measured. The accumulated change from the baseline level is ΔR₁+ ΔR₂It becomes. Similarly, the third measurement point t_ThreeThen the measured change in the ratio from the previous point is ΔR_ThreeAnd the accumulated change from the baseline level is ΔR₁+ ΔR₂+ ΔR_ThreeIt becomes. As can be seen from the graph, various values of ΔR, especially for breath tests lasting a significant amount of time compared to the stability level of the device._nCan be significant, even more so with accumulated ΔR.
[0175]
According to a preferred embodiment of the present invention, such errors can be substantially reduced by collecting a sample pair for each measurement point. For example, time t₁, One sample of the collected sample pair is at time t₀Used to compare with baseline reference sample measured at The second sample of the sample pair is time t₂Saved without doing anything until time t₂Is used as a reference sample for one of the sample pairs collected in. Thus, the measurement ratio ΔR due to instrument drift.₂Changes in are negated. Because at time t₁Sample from time t₂Essentially the same in the instrument, ie at time t₂This is because the comparison is made under the conditions existing in the equipment. Similarly, time t₂A second sample stored from time t_ThreeBy comparing with the sample from_ThreeIt becomes possible to disable the obvious shift. Similar arguments apply to all consecutive measurement points of the breath test.
[0176]
The above description is slightly simplified in that it takes an extremely short time to measure the ratio of each sample and assumes that both samples are measured simultaneously at each time point. In practice, the measurement of each ratio takes time Δt, for example at point 2 at time t₁Measurement of the ratio of the reference sample stored from time t₂This is performed at time Δt, faster than measuring one of the sample pairs collected in step. During this time Δt, the drift of the device continues, resulting in a time t₂The ratio r measured in₂Is the time (t₂+ Δt) differs from the ratio measured by the amount Δr. However, since the time Δt for measuring the ratio is generally significantly shorter than the elapsed time between successive measurement points, the use of the sample-to-measurement method according to this preferred embodiment of the invention significantly increases the accuracy. Also, immunity from instrument drift increases.
[0177]
Furthermore, the sample pairing method according to this preferred embodiment of the present invention still significantly improves the measurement even when the time it takes to dilute each sample to the target concentration and measure the concentration achieved. Such a process is performed such that samples are compared at the same concentration. The process of dilution and concentration measurement actually takes much longer than the time Δt to perform the ratio measurement itself. If both the reference sample collected from the previous measurement point and the sample currently being measured, the dilution and concentration measurement procedure is performed in a minimum amount of time between the measurement points, the ratio When the time point is reached, the sample has already been diluted to the target concentration and is ready to be measured immediately. Moreover, the time difference between the comparative measurements is less than Δt.
[0178]
This preferred method of using RCIR parameters to collect and measure sample pairs and calculate relative changes in the isotope ratio of the sample is advantageous and is applicable to all types of breath tests. This type of breath test involves using a bag for sample collection and then analyzing the breath test that is analyzed at a time and location that is not necessarily related to the time and location of the sample collection. It includes both a breath test performed in real time, connected to the breath test device so that the breath can be monitored almost continuously by the breath test device.
[0179]
(C) Baseline identification method
In the known art, a baseline is determined by detecting the isotope ratio of a single measurement taken from a single breath sample or group of samples obtained prior to ingestion of the labeled substrate. Singles obtained due to instrument drift or high noise levels, or due to physiological “noise” in exhaled breath supplied by the patient when continuous exhalation gives significantly different isotope ratios for clinical reasons The above method may produce inaccurate results if the baseline points of are incorrect.
[0180]
In order to overcome such sources of potential inaccuracy, according to another preferred embodiment of the present invention, the quality of the measured baseline points is reviewed by the action of the baseline identification method, If necessary, one or more additional baseline points are measured before the patient ingests the labeled substrate.
[0181]
According to a first additional preferred embodiment relating to a baseline measurement, a self-diagnostic procedure operable within the instrument is used, for example, with a low standard deviation in the variability of separate results forming the first baseline measurement point. If the control system indicates that the measured point quality is high, as determined by being present at, or by achieving a carbon dioxide concentration that approximates the target value, Conclude that is sufficiently accurate.
[0182]
According to another preferred embodiment, a second baseline measurement is taken. If two measurements are within a predetermined value of each other, it is estimated that there is no interference with the baseline measurement, both instrumentally and physiologically, and a simple average of the two values is It is preferably used. On the other hand, if a discrepancy is detected between two values, or if one of these points is suspected to be of poor quality, for example as determined by the criteria described above, there are many possibilities. appear. Preferably, low quality points are discarded and only good points define the baseline level. Alternatively and preferably, the system may require a measurement of the third baseline point. It is preferable to determine which of the measurement results to use based on the result of the third baseline point. If the first two values appear to vary due to noise problems, the method takes a simple average of all three values. Alternatively, if it is clear from the third measurement that one of the first two values is significantly different from the other two, then one of the first two values is rejected as a bad value. can do.
[0183]
According to another preferred embodiment of the present invention, the baseline measurement is performed to speed up the progress of the examination. Thus, for example, the second point is preferably collected before the analysis of the first point is completed. If it is clear that the first point is of poor quality and cannot be used before the second point measurement is completed, the calculation routine will collect the third baseline sample before the second point measurement is completed. Request.
[0184]
According to another preferred embodiment of the invention, in order to speed up the test, before knowing the result of the second measurement but after collecting the breath sample for the second baseline measurement The patient is provided with a labeled substrate for ingestion. In this case, for example, by the standard deviation of the discrete points forming the measured value or the CO achieved₂If you check the quality of a measurement, as determined by the accuracy of the target concentration, and you find that one of the measurements is not accurate, discard that measurement in calculating the baseline. Can do. If the quality of both measurements is good, the average of these values may be used.
[0185]
(D) Threshold usage
Breath tests to detect specific clinical conditions, like many other diagnostic tests, rely on achieving a level that indicates a particular result or a positive test result. Providing a definitive diagnosis of the absence of the sought clinical condition, in other words defining a negative result, is a more difficult task.
[0186]
The work function of the breath test is to identify any changes that occur in the isotope ratio of the subject's breath sample components that are clinically significant in relation to the effect sought. The criteria for this determination, as used in many of the prior art, is whether the DoB has exceeded a predetermined threshold level at or within the time allotted for the examination. If the result is positive, the judgment is simpler, even if there is still some suspicion when the threshold crossing is not firm, such as when a moderate upward drift of the DoB value is obtained. is there. However, it is more difficult to make a firm diagnosis that the result is really negative if the DoB is wandering between the baseline and the threshold, and sometimes this DoB is moved beyond the threshold, possibly due to random noise. is there. Since ulcers are prevalent in a significant proportion of the population and the upper gastrointestinal tract has a similar associated condition, the interpretation of a negative result is H. Of particular importance in the urea breath test commonly used to detect the presence of H. pylori.
[0187]
One solution to this problem is to allow the test to last for a longer time, thereby determining whether the result remains negative. However, this is inconvenient for the patient and unnecessarily occupies expensive equipment that could be used to examine another patient. Therefore, it is important to take steps to define an optimal breath test threshold level that allows clear results, especially negative results, to be obtained in a minimum amount of time.
[0188]
In order to achieve these objectives and to achieve the highest sensitivity and specificity with the shortest possible measurement time, a breath test analyzer according to another preferred embodiment of the present invention provides a patient breath test. Do not use fixed criteria to determine if changes in isotope ratio are clinically significant. Instead, the criteria are changed during the course of the test according to many factors that act during the test. This factor includes, for example, the elapsed time of the test, the noise level of the device performing the test, and the physiological results of the test.
[0189]
Furthermore, while traditionally used measurements of isotope ratio changes were ratio levels relative to the baseline level, according to another preferred embodiment of the present invention, the measurements are Rather, it may be a change with respect to the previous measurement point, or the rate of change of the isotope level, or another property that can be used to plot the course of the change.
[0190]
In the preferred embodiment of the present invention presented here to illustrate these novel measures, a threshold utilization method is used to determine whether sufficient data has been accumulated to determine the completion of the test. Uses real-time test results. Such an identification is achieved by using a dynamic threshold level. The value of this level can be varied as a function of one or more of the following quantities by threshold utilization during the course of the measurement:
(I) the nature of the accumulated data, ie a function of whether the test gives a well-defined result;
(ii) a function of the level and trend of the results obtained;
(iii) a function of the standard deviation of the accumulated data, and
(iv) A function of the noise and drift levels of a particular instrument being used at that particular point in time.
[0191]
According to yet another preferred embodiment, two thresholds can be utilized, an upper and lower threshold. These thresholds converge as the significance of the collected data becomes apparent.
[0192]
The method of determining the use of the variable threshold can distinguish between the start of the test after the oral activity has subsided and the test in progress. Early in the test before accumulating a large amount of data, the point is clearly above the baseline, suggesting a positive result, or suggesting a negative result, to determine the definitive result. Must be very close to the line. As the test progresses and the physiological results of a large number of accumulated measurement points are taken into account, the threshold criteria to be used should become more statistically based on the accumulated data.
[0193]
The results of these two approaches are shown in FIG. FIG. 6 illustrates a preferred method using a double dynamic threshold criterion. In FIG.₀A plot of threshold values used as a function of time elapsed since ingestion of the isotope-labeled substrate at is shown. Time t₀T from the start of inspection at₁In region 500, the breath sample is generally not taken into account in determining whether the upper threshold has been reached. This is because oral activity may be present due to the substrate being debilitated by bacteria present in the patient's mouth. On the other hand, if the oral activity detection system detects that no significant oral activity is present, it can be determined that the upper threshold is crossed, for example, at time t.₀Even those from can take into account the rising results. Results close to the baseline can generally always be taken into account. This is because it is clear that such results are not affected by the presence of oral activity, even if they exist.
[0194]
Time t₁If oral activity is present after the passage of time, this activity will subside, and if all of the collected exhaled air is taken into account for the calculation of the test results, two thresholds, the upper threshold T_u506 and lower threshold T_l508 is used. If very little data is stored throughout region 502, T_uAnd T_lThe significantly different values of 8δ and 2δ are used in the preferred embodiment of FIG. The lower result 2δ is considered a negative result, whereas the upper result 8δ is considered a positive result. T_uAnd T_lThe results that exist in the region between are unclear and require more data to be accumulated. According to another preferred embodiment, the threshold level does not have to be constant in this region,₁Starts at a large distance and converges slowly over time. This is as shown by another upper threshold curve 507.
[0195]
An important aspect of this preferred embodiment is the time t, which can be only 4 minutes after administration of urea.₁By the time the result is reached, it is already possible to make a clear diagnosis of positive or negative if the results obtained are sufficiently deviated from the intended baseline, ie 8 δ and 2 δ in the preferred embodiment described That is. A preferred criterion for a clear diagnosis is that the diagnosis is positive if two points are obtained above the upper threshold, excluding any points below the lower threshold. Similarly, if there are two points below the lower threshold, excluding any points above the upper threshold, this is a sufficient criterion to provide a negative diagnosis. The more rigorous and preferred criteria for a negative diagnosis, bearing in mind the difficulties described above in determining whether a result is truly negative, is the presence of three or four consecutive points after urea administration It is. These points are below the lower threshold or, on average, below this threshold, have a standard deviation of less than 1δ and a slope of less than 0.1δ per minute, Have no significant drift or tilt. Qualitatively, this can be used to identify negative results faster than any conventional method on instruments that are known to operate historically stable when measuring a DoB plot that should be almost flat. It is suggested that. Thus, in terms of the speed at which a diagnosis can be provided, one aspect of the preferred embodiment of the breath test of the present invention shows a significant difference in both positive and negative results from previous instrument and method embodiments.
[0196]
In the case of the embodiment of FIG. 6, the time t shown in 6 minutes.₂If enough points have accumulated after the lapse of time, the standard deviation of the result should drop, and the physiological result of the test should be sufficiently obvious if it is critical in either direction So the thresholds can be gradually moved closer together and moved in a direction that provides the highest sensitivity and specificity for the ongoing test. Time t when closing of the thresholds starts₂And the rate of closure of the thresholds 510, 512 itself and the rate of change of any level common to both thresholds is determined by the data itself or predetermined. If the point has a standard deviation that converges rapidly from the optimal curve, the result is that the threshold is quickly closed and moved. The reverse is true if the standard deviation converges slowly. Again, the time t determined by the degree of variation of the points_ThreeLater, the two thresholds converge to one threshold 514 at the traditionally used level, in this example 5δ. From this point in time, diagnosis is made based on the results located above or below this threshold.
[0197]
On the other hand, if the data points still vary and their average level is close to 5δ, an error message is displayed and the test is terminated without significant results.
[0198]
During use, the threshold utilization method shown in FIG. 6 preferably operates as follows. Subjects with elevated DoB results that do not exceed 8δ after 6 minutes will be re-evaluated after 8 minutes with a threshold of 7δ, and if this threshold is not exceeded, 10 minutes later, with a threshold of 6δ, Such an evaluation is carried out until 5δ is used. Similarly, subjects with an unidentified DoB tendency that do not fall below 2δ after 6 minutes will be re-evaluated after 8 minutes with a threshold of 3δ, and if not below this threshold, 10 minutes later, Such an evaluation is carried out until a 5δ value, which is evaluated at a threshold and is used traditionally, is reached.
[0199]
As the time of the test progresses and the accumulated data reflects the physiological reality of the breath test mechanism, so that the DoB of a positive subject increases with time, the threshold 151 used is the test time It becomes possible to rise slowly with the continuation of.
[0200]
According to another preferred embodiment, the lower threshold continues to exist independently, instead of combining with the upper threshold to form a single threshold level. This is illustrated by another preferred lower threshold 516 in FIG. This lower threshold 516 remains constant at a level somewhat above that shown in the example 4δ, or slowly with time as the distinction between negative and positive results becomes more apparent. Descent.
[0201]
The effectiveness of using variable thresholds in accordance with the preferred embodiment described above is that the results obtained with an exhalation tester incorporating such threshold embodiments are compared with the results obtained by standard monitor test methods. Verified by. H. In the case of the H. pylori breath test, such standard monitoring methods are performed by endoscopic collection of biopsy material from the patient's stomach, followed by histological examination of the tissue or culture of existing bacteria.
[0202]
According to another preferred embodiment of the present invention, the threshold used is related to the self-diagnostic output of the system. For devices that give poor results, such as high noise levels or systematic noise patterns, or slopes in the results, threshold usage is a wide range of initial thresholds: a relatively high upper threshold and a lower lower threshold. Use. For instruments that give good results with low noise levels or low levels of drift, the upper and lower threshold levels and the difference between these threshold levels can all be reduced to define negative results. The number of points below the required threshold can then be reduced. In this way, it is possible to define a test result as negative or positive earlier than with a fixed threshold.
[0203]
According to another preferred embodiment of the present invention, threshold utilization is used to determine whether a set of measured points is considered to give a clear test result. A quadratic optimal combined polynomial is preferably constructed so as to functionally approximate the plot of points obtained in one test. Only those points measured following effective termination of oral activity are used in the construction of this polynomial. The weighted standard deviation of these points from the calculated polynomial curve is then calculated. The weighting is performed so that the deviation from the polynomial curve is taken as it is for the points above the baseline, for example, less than 5δ. For points above 5δ above the baseline, the influence of random noise on such measurements is much less so that the calculation method uses polynomials as effective error values for the purpose of calculating the weighted standard deviation. Take only 20% of the deviation from the point. If such a weighted standard deviation is greater than 1.5σ, the measured value is considered problematic because of the large variation in results.
[0204]
In addition to the standard deviation criteria, there are other preferred criteria for rejecting measurements as inconclusive. An example of such a preferred criterion is that at least two of the five measured points are within threshold limits, eg, 3δ-7δ above the baseline, at the same time as the last Is used when the measured point is less than 10δ above the baseline, indicating no strong positive results. Even if only the last point appears to give a positive result, the calculation routine rejects the measurement as it currently exists. This is because uncertainty is introduced by the above-mentioned “two out of five” criteria.
[0205]
In some parts of the specification, procedures and calculations have been described for urea breath tests to detect Helicobacter pylori in the upper gastrointestinal tract, but of course, this test has many It is just an example of a diagnostic test and the present invention is It is not limited to the preferred illustrative example that results from the H. pylori detection breath test.
[0206]
It will be apparent to those skilled in the art that the present invention is not limited to what has been particularly shown and described. Rather, the scope of the present invention includes combinations and subcombinations of the various components described above, as well as variations and modifications of these components. Such combinations, changes and modifications can be easily considered by those skilled in the art after reading the above description, and are not present in the prior art.
[Brief description of the drawings]
FIG. 1 shows the components of an exhalation tester disclosed in PCT International Publication No. 99/14576 (WO99 / 14576) pamphlet incorporating an intermediate chamber system for storing and handling exhalation samples. Schematic block diagram.
FIG. 2 is a perspective view showing an NDIR molecular correlation spectrometer of the type used in the breath tester of FIG.
FIG. 3 is a flow diagram showing the main steps of a preferred embodiment of a calibration procedure for operating a breath tester.
4A-4E can be accurately interpreted using a variety of typical breath test results, ie, a virtually continuous sampling and analysis method according to a preferred embodiment of the present invention. However, FIG. 4 shows plots of various typical breath test results that may be misinterpreted using conventional methods of collecting and analyzing individual bags of sample breath.
FIG. 5 is a graph showing the use of a method of comparing consecutively collected sample pairs with each other rather than comparing with a baseline of a reference sample.
FIG. 6 shows the threshold used to determine when a change in isotope ratio provided a definitive result as a function of time elapsed since ingestion of the isotope-labeled substrate. It is a graph to show.

Claims (47)

How to perform a breath test:
Prior to the intake test, to measure the isotopic ratio of the at least one breath sample of the subject is determine whether it is clinically significant, the steps of Ru decided predefined criteria,
Measuring the isotope ratio of at least one inhaled sample of the subject to obtain a measurement value;
Comparing the measurement with the reference;
Changing the criteria if it is difficult to determine if the measurement is clinically significant;
Re-comparing the measurement with a modified standard to assess whether the measurement is clinically significant;
A breath test method comprising:   The breath test implementation method according to claim 1, wherein the change in the measurement value includes a deviation of the isotope ratio from a measurement value of at least one previous sample of the subject.   The breath test implementation method according to claim 2, wherein the measurement value of at least one previous sample of the subject is a baseline measurement value.   The breath test execution method according to claim 1, wherein the change in the measurement value includes a change rate of the isotope ratio.   5. The method for performing a breath test according to claim 1, wherein the criterion is a function of an elapsed time of the test.   5. The breath test execution method according to claim 1, wherein the reference is a function of a noise level of a device that performs the test.   5. A method for performing a breath test according to any one of claims 1 to 4, wherein the criterion is a function of the physiological result of the test. The breath test is:
Performing a first measurement of the isotope ratio of at least a first breath sample of the subject;
Performing a second measurement of the isotope ratio of at least a second breath sample of the subject;
Determining when the value of the second measurement indicates a deviation from the value of the first measurement sufficient to produce a clinically significant result of a breath test;
A breath test method, characterized in that the level of sufficient deviation can vary during the breath test.   The breath test method according to claim 8, wherein the first measurement value of the isotope ratio of at least a first breath sample of the subject is a baseline measurement value.   9. The breath test method of claim 8, wherein the level of sufficient deviation is at least a function of the time elapsed since the subject ingested the identified substrate.   The breath test method according to claim 8, wherein the level of sufficient deviation is at least a function of a physiological analysis result of at least one of the samples.   The breath test method according to claim 8, wherein the level of sufficient deviation is at least a function of the nature of the result obtained in the breath test.   The breath test method according to claim 12, wherein the nature of the result is at least a function of a standard deviation of the spread of results in the breath test.   The breath test method of claim 12, wherein the nature of the result is at least a function of a noise level present in the result.   13. The breath test method of claim 12, wherein the nature of the result is at least a function of device drift present in the result.   The breath test method according to claim 8, wherein the level of sufficient deviation occupies a range of values between an upper threshold and a lower threshold.   The breath test method according to claim 16, wherein the upper threshold value and the lower threshold value converge as the test progresses.   The breath test method according to claim 8, wherein the first measurement of the isotope ratio of at least a first breath sample of the subject is performed only after the oral activity has remarkably subsided.   17. The breath test method according to claim 16, wherein the presence of at least two measurements that exceed the upper threshold within a predefined time period indicates a positive result of the breath test.   The breath test method according to claim 16, wherein the presence of at least two consecutive measurements above the upper threshold indicates a positive result of the breath test.   17. The breath test method of claim 16, wherein the presence of at least two measurements above the upper threshold indicates a positive result of the breath test in combination with the absence of measurements below the lower threshold.   17. The breath test method of claim 16, wherein the presence of at least two measurements that fall below the lower threshold within a predefined time period indicates a negative result of the breath test.   17. The breath test method of claim 16, wherein the presence of at least two consecutive measurements below the lower threshold indicates a negative result of the breath test.   17. The breath test method of claim 16, wherein the presence of at least two measurements below the lower threshold indicates a negative result of the breath test in combination with the absence of any measurement above the upper threshold.   There are at least two consecutive measurements below the upper threshold, the measurements having a difference less than a predefined difference in delta values between the three measurements; and 17. The presence of the at least two consecutive measurements indicates a negative result of the breath test when having a slope that is less than a predefined average slope between measurements. Breath test.   If there are at least two consecutive measurements below the lower threshold and the measurements have a slope that is less than a predefined average slope between the measurements, the at least two consecutive measurements 17. A breath test method according to claim 16, wherein the presence of a typical measurement indicates a negative result of the breath test. In a breath test for determining the presence of a clinically significant condition in a subject, the breath test includes:
Measuring a change in baseline isotope ratio in a plurality of samples consisting of exhaled breath exhaled from the subject after effective cessation of oral activity;
Determining a polynomial that approximates a function plot of the measured value with time;
For measurements that exceed the baseline by more than a predefined amount, a predetermined fractional portion of the measurement is taken, whereas more than the predefined amount by the baseline. Calculating a weighted standard deviation of the measured value from the polynomial, where the entire measured value is taken for measured values not exceeding
Determining whether the weighted standard deviation exceeds a predefined level;
Breath test consisting of The breath test is:
Performing an isotope ratio measurement of at least a first breath sample of the subject;
Determining when the value of the measurement shows a deviation from the baseline measurement sufficient to produce a clinically significant result of the breath test;
Consisting of
The deviation consists of uncertain upper and lower threshold bands, the width of which is the elapsed time of the breath test, the standard deviation of the physiological spread of the result, the dynamic characteristics of the physiological change of the isotope ratio, the breath Related to at least one parameter selected from the group consisting of the number of time points measured in the test, the environmental conditions present during the breath test, and the level of noise and / or drift of the device performing the breath test To
A breath test method characterized by that. How to determine the reliability of a breath test:
Obtaining results from the breath test;
Selected from the group consisting of the level of instrument noise and / or drift, the standard deviation of the physiological spread of the results, the dynamic characteristics of the physiological change of the isotope ratio, and the elapsed time since ingestion of the labeled substrate Defining the reliability parameter by combining at least one of the selected criteria;
Using the reliability parameter to evaluate the result of the breath test according to predefined reliability criteria;
A method for determining the reliability of a breath test.   30. The method of claim 29, wherein the reliability parameter is considered in determining when a clinically significant result was obtained to complete the test.   30. The method of claim 29, wherein the reliability parameter is output along with a breath test result. In a breath test apparatus comprising a tube for collecting a breath sample from an insured and a gas analyzer for measuring an isotope ratio of the breath sample,
The gas analyzer monitors the change in the isotope ratio of the gas in the breath sample exhaled from the subject virtually continuously, and according to the current results of the test, the test is a clinically significant conclusion. Breath test equipment where it is determined that   33. The breath test apparatus according to claim 32, wherein the breath test apparatus comprises a signal to indicate that a clinically significant conclusion of the breath test has been determined.   34. A breath test apparatus according to claim 33, wherein the signal is a visible signal.   34. A breath test apparatus according to claim 33, wherein the signal is an audible signal.   36. The breath test apparatus of claim 35, wherein the signal also indicates a clinically significant conclusion nature of the breath test.   33. The breath test apparatus of claim 32, wherein the test conclusion is substantially independent of dynamic physiological effects that occur on the subject as a result of background conditions.   38. A breath test apparatus according to claim 37, wherein the background condition is a result of treatment with medication.   38. The breath test apparatus of claim 37, wherein the background condition is a result of food intake prior to performing a breath test.   40. The breath test apparatus of claim 39, wherein the need for fasting by the subject prior to testing is eliminated.   The conclusion of the test for the subject treated with gastrointestinal medication is more reliable than using a corresponding breath test that does not monitor the change in isotope ratio substantially continuously, 33. A breath test apparatus according to claim 32.   33. The breath test apparatus of claim 32, wherein the test conclusion is obtained more reliably than is obtained by a corresponding breath test apparatus that does not monitor the change in isotope ratio substantially continuously.   33. The breath test apparatus of claim 32, wherein the test conclusion is obtained more quickly than is obtained by a corresponding breath test apparatus that does not monitor the change in isotope ratio substantially continuously.   33. A breath test apparatus according to claim 32, wherein the current result of the test allows a positive result to be determined even if the isotope ratio does not clearly exceed a predetermined threshold level.   33. The breath test apparatus of claim 32, wherein the current result of the test allows a negative result to be determined even if the isotope ratio exceeds a predetermined threshold level.   46. The breath test apparatus of claim 45, wherein the negative result is also determined if the isotope ratio exceeds the predetermined threshold level due to instrument drift.   33. A breath test apparatus according to claim 32, wherein the current result of the test allows a negative result to be determined by detecting a correlation between the isotope ratio and instrument drift.

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