JP2006300843A - Method for verifying state of suction - Google Patents
Method for verifying state of suction Download PDFInfo
- Publication number
- JP2006300843A JP2006300843A JP2005125756A JP2005125756A JP2006300843A JP 2006300843 A JP2006300843 A JP 2006300843A JP 2005125756 A JP2005125756 A JP 2005125756A JP 2005125756 A JP2005125756 A JP 2005125756A JP 2006300843 A JP2006300843 A JP 2006300843A
- Authority
- JP
- Japan
- Prior art keywords
- suction
- pressure data
- yci
- pressure
- state
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000012937 correction Methods 0.000 claims abstract description 50
- 239000007788 liquid Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000012886 linear function Methods 0.000 claims description 3
- 230000002547 anomalous effect Effects 0.000 abstract 1
- 230000001419 dependent effect Effects 0.000 abstract 1
- 238000012795 verification Methods 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 49
- 230000002159 abnormal effect Effects 0.000 description 25
- 210000002966 serum Anatomy 0.000 description 22
- 238000005070 sampling Methods 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 4
- 239000013074 reference sample Substances 0.000 description 4
- 230000002411 adverse Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000012887 quadratic function Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
Images
Landscapes
- Automatic Analysis And Handling Materials Therefor (AREA)
Abstract
Description
本発明は、負圧源に接続された吸引管の先端を介して所定量の液体を吸引するときの吸引状態を確認する方法に係り、とくに血液等の生体液試料のための自動分析におけるサンプリングの吸引状態を確認する方法に関する。 The present invention relates to a method for confirming a suction state when a predetermined amount of liquid is sucked through a tip of a suction tube connected to a negative pressure source, and more particularly, sampling in automatic analysis for a biological fluid sample such as blood. The present invention relates to a method for confirming the suction state.
液体試料とりわけ血液等の生体液体試料のための自動分析において、試料の一部をサンプリングプローブによって吸引保持し、分析のための反応容器に分注することが一般におこなわれている。分注量が分析結果に影響を及ぼす免疫測定法等の分析方法を採用するとき、サンプリングの正確性・精度は重要である。血清、血漿等の血液試料をサンプリングプローブによって吸引する際、血液試料中に混在し得るフィブリン等の固形物がサンプリングプローブの先端や吸引管路内を閉塞して、サンプリングの正確性・精度に悪影響を及ぼすことがしばしば起こる。また、吸引動作の不具合やノズルチップの装着不良によって、気泡の混入や液漏れが生じることがある。 In an automatic analysis for a liquid sample, particularly a biological liquid sample such as blood, a part of the sample is generally sucked and held by a sampling probe and dispensed into a reaction container for analysis. When adopting an analysis method such as an immunoassay in which the amount of dispensing affects the analysis result, the accuracy and precision of sampling are important. When a blood sample such as serum or plasma is aspirated by a sampling probe, solid matter such as fibrin that may be mixed in the blood sample blocks the tip of the sampling probe or the inside of the suction pipe, adversely affecting the accuracy and precision of sampling. Often occurs. In addition, air bubbles may be mixed in or liquid leakage may occur due to a suction operation failure or nozzle tip mounting failure.
吸引ポンプ等の負圧源に接続されたサンプリングプローブを用いる際、サンプリングプローブまたは流路の内部圧力を経時的にモニターすることによりサンプリングの適否を確認する手段またはその手段を備えた分注装置が多く開示されている。たとえば、液体吸引中の吸引管内部の圧力の時間に対する一次微分値を指標とするもの（特許文献１参照）や圧力の時間に対する積分値を指標とするもの（特許文献２参照）がある。また、正常な吸引がおこなわれたときの圧力変化曲線の上限と下限からなる正常吸引圧力枠なるものを指標とするものも開示されている（特許文献３参照）。これらの指標は試料の粘性に依存し、粘性が試料ごとに大きく異なる血清等の試料に対しては、正常な吸引に対して異常吸引と判定する誤りを犯すおそれがある。すなわち、粘度の高い試料をサンプリングプローブ内に吸引する場合、たとえばシリンジポンプの動きに対して試料の移動には時間的遅れが生じるため、吸引管内部の負圧が一時的に強まる傾向があるが、所定時間内に必要量が吸引できるならば、これを異常吸引と判定すべきではない。 When using a sampling probe connected to a negative pressure source such as a suction pump, means for confirming the suitability of sampling by monitoring the sampling probe or the internal pressure of the flow passage over time, or a dispensing apparatus equipped with the means Many have been disclosed. For example, there are an index using a first derivative value with respect to time of pressure inside the suction pipe during liquid suction (see Patent Document 1) and an index using an integral value with respect to time of pressure (see Patent Document 2). Moreover, what uses as an index a normal suction pressure frame composed of an upper limit and a lower limit of a pressure change curve when normal suction is performed is also disclosed (see Patent Document 3). These indices depend on the viscosity of the sample, and for samples such as serum whose viscosities vary greatly from sample to sample, there is a risk of making an error in determining normal suction as abnormal suction. That is, when a sample with high viscosity is sucked into the sampling probe, for example, there is a time delay in moving the sample with respect to the movement of the syringe pump, so the negative pressure inside the suction tube tends to temporarily increase. If a necessary amount can be sucked within a predetermined time, this should not be determined as abnormal suction.
試料の粘性に依存しない異常吸引の判定方法として、特許文献４は圧力変化曲線の時間による二次微分値を指標とすることを提案している。この方法によれば粘性に依存しない安定した閉塞しきい値および吸引不足しきい値が得られるとのことであるが、二次微分の曲線からは吸引異常の程度が直感的に把握しにくいきらいがある。特許文献５は、粘度の高い液体を吸引するとき、管路内の圧力は吸引中に大きく負圧側に振れるものの、正常に吸引されたときは吸引動作停止後に、粘度の低い液体を吸引したときと同じ圧力レベルに復帰することを利用して、吸引後の所定時期の圧力を詰まりの判別の指標とすることを提案している。しかし、最終的に高粘度試料の吸引量が確保されたとしても、不完全な閉塞物が吸引された場合、この吸引された閉塞物がその後の分注操作または分析反応中に悪影響を及ぼすことがありうる。 As a method for determining abnormal suction that does not depend on the viscosity of a sample, Patent Document 4 proposes to use a second-order differential value with time of a pressure change curve as an index. According to this method, it is possible to obtain a stable occlusion threshold and an insufficient suction threshold that do not depend on viscosity, but it is difficult to intuitively grasp the degree of abnormal suction from the second derivative curve. There is. In Patent Document 5, when sucking a high-viscosity liquid, the pressure in the pipe line greatly fluctuates during suction, but when sucking normally, when sucking a low-viscosity liquid after stopping the suction operation It is proposed that the pressure at a predetermined time after suction is used as an index for determining clogging by utilizing the return to the same pressure level as in the above. However, even if the suction amount of the high-viscosity sample is finally secured, if the incomplete blockage is sucked, the sucked blockage may adversely affect the subsequent dispensing operation or analytical reaction. There can be.
本発明は試料の粘性の影響を適度に許容し、かつ吸引中の完全閉塞、不完全閉塞、吸引量不足等の種々の要因に由来する異常吸引を総合的に検知し、サンプリングプローブの吸引状態を高精度に確認する方法を提供することを目的とする。 The present invention moderately allows the influence of the viscosity of the sample, and comprehensively detects abnormal suction resulting from various factors such as complete blockage, incomplete blockage, insufficient suction amount during suction, and the sampling probe suction state An object of the present invention is to provide a method for confirming a high accuracy.
本発明者らは、正常な吸引がおこなわれた圧力変化曲線と、試料を吸引したときの圧力変化曲線との相似性により吸引状態を総合的に評価するに際して、吸引管内部の圧力に及ぼす試料粘度等の影響が吸引経過時間に依存すると仮定し、鋭意検討を重ねて本発明を完成した。 When the present inventors comprehensively evaluate the suction state based on the similarity between the pressure change curve in which normal suction is performed and the pressure change curve when the sample is sucked, the sample affects the pressure in the suction pipe. Assuming that the influence of viscosity and the like depends on the elapsed time of suction, the present invention was completed through extensive studies.
すなわち本発明は、負圧源に接続された吸引管の先端を介して所定量の液体を吸引するときの吸引状態を確認する方法であって、基準とする吸引状態において吸引経過時間ｔｉ（ｉ＝１，２，・・・，ｎ）に対して前記吸引管内部の圧力データｙｉ（ｉ＝１，２，・・・，ｎ）を取得することと、確認する対象の吸引状態において吸引経過時間ｔｉ（ｉ＝１，２，・・・，ｎ）に対して前記吸引管内部の圧力データＹｉ（ｉ＝１，２，・・・，ｎ）を取得することと、前記圧力データｙｉを吸引経過時間に依存する補正係数によって変換した圧力データｙｃｉ（ｉ＝１，２，・・・，ｎ）、または前記圧力データＹｉを吸引経過時間に依存する補正係数によって変換した圧力データＹｃｉ（ｉ＝１，２，・・・，ｎ）を得ることと、ＹｉとｙｃｉとからまたはｙｉとＹｃｉとから、残差２乗和Σ（Ｙｉ−ｙｃｉ）２の最小値またはΣ（ｙｉ−Ｙｃｉ）２の最小値を算出することと、算出された前記残差２乗和の最小値または算出された残差２乗和の最小値の平方根を閾値に対して比較することと、この比較結果に応じて吸引状態の正否を確認することと、を含む。 That is, the present invention is a method for confirming a suction state when sucking a predetermined amount of liquid through the tip of a suction pipe connected to a negative pressure source, and the suction elapsed time ti (i = 1, 2,..., N) Acquiring the pressure data yi (i = 1, 2,..., N) inside the suction pipe and the suction process in the suction state of the object to be confirmed Obtaining the pressure data Yi (i = 1, 2,..., N) inside the suction pipe with respect to time ti (i = 1, 2,..., N); Pressure data yci (i = 1, 2,..., N) converted by a correction coefficient depending on the suction elapsed time, or pressure data Yci (i) converted from the pressure data Yi by a correction coefficient depending on the suction elapsed time. = 1, 2,..., N), Yi and y and a i Tokara or yi and Yci, residual square sum Σ (Yi-yci) the minimum value of 2 or Σ (yi-Yci) and calculating the minimum value of 2, the residual squared calculated Comparing the minimum value of the sum or the square root of the calculated minimum value of the residual sum of squares with respect to the threshold value and confirming whether the suction state is correct or not according to the comparison result.
本発明の圧力データは、複数の吸引経過時間に対して取得されるために複数の値を含み、吸引経過時間に対する圧力変化曲線として表すことができる。したがって基準とする吸引状態の圧力データを基準の圧力変化曲線として、確認する対象の圧力変化曲線と比較することができ、これらの相似性により吸引状態を評価することができる。なお本明細書で、圧力変化曲線とは、時間の経過に連れて変化しうる圧力データの集合または部分集合をいう。圧力変化曲線といっても連続的曲線的に変化する滑らかな曲線に限定されるものではなく、とびとびの圧力−時間データからなり折れ線の形状をなすものも含まれる。 Since the pressure data of the present invention is acquired for a plurality of suction elapsed times, the pressure data includes a plurality of values and can be expressed as a pressure change curve with respect to the suction elapsed time. Therefore, the pressure data of the reference suction state can be compared with the pressure change curve to be confirmed as a reference pressure change curve, and the suction state can be evaluated by their similarity. In this specification, the pressure change curve refers to a set or a subset of pressure data that can change over time. The pressure change curve is not limited to a smooth curve that changes in a continuous curve, but also includes a pressure-time data and a polygonal line shape.
基準とする吸引状態の圧力データは、吸引プローブの詰まりや空吸いのない正常な吸引がおこなわれたときに取得された圧力データを用いることができる。基準とする吸引状態の圧力データは１回の実験から得られた圧力変化曲線でもよいし、複数回の実験から取得し、個々の吸引経過時間に対する圧力データの平均値をとったり、曲線当てはめの統計的手法を用いる等して得られた圧力変化曲線でもよい。 The pressure data acquired when normal suction without clogging of the suction probe or empty suction is performed can be used as the reference pressure data of the suction state. The pressure data of the suction state as a reference may be a pressure change curve obtained from a single experiment, or it may be obtained from a plurality of experiments, and an average value of pressure data for each elapsed suction time may be taken. It may be a pressure change curve obtained by using a general method.
本発明の方法を実際に適用する実験条件において、吸引状態を大きく変える因子、たとえば吸引に要する時間、吸引速度、吸引量、サンプリングプローブの形状等を変える予定があるのならば、それらの因子ごとに基準の圧力変化曲線を求めておくのが望ましい。一方、吸引状態を変える可能性をもつ因子ではあるが、その因子ごとに基準の圧力変化曲線を求めるのが実際には困難である場合には、その因子をいろいろと変えて実験し、圧力変化曲線にどの程度影響を及ぼすかをあらかじめ把握しておくのが望ましい。たとえば、自動分析装置のサンプリングプローブを使用する場合には、同種の別個体である複数台の装置やサンプリングプローブを用いて複数の基準の圧力変化曲線を求める。このように、正常な吸引がおこなわれる種々の条件で多くの基準の圧力変化曲線を求めておくことは、吸引状態の正否を判定するための閾値の設定のためにも有用である。また、あらかじめ基準の圧力変化曲線および閾値を求めておけば、実際の測定を行なう際には、確認する対象の圧力変化曲線を取得し、すでに取得した基準の圧力変化曲線および閾値を使用して本発明の方法を実施することができる。 In the experimental conditions in which the method of the present invention is actually applied, if there are plans to change factors that greatly change the suction state, for example, the time required for suction, the suction speed, the suction amount, the shape of the sampling probe, etc. It is desirable to obtain a reference pressure change curve. On the other hand, if it is a factor that has the possibility of changing the suction state, but it is actually difficult to obtain a standard pressure change curve for each factor, experiment with various factors to change the pressure change It is desirable to know in advance how much the curve will be affected. For example, when a sampling probe of an automatic analyzer is used, a plurality of reference pressure change curves are obtained using a plurality of devices or sampling probes which are the same kind of separate bodies. Thus, obtaining many reference pressure change curves under various conditions under which normal suction is performed is useful for setting a threshold value for determining whether or not the suction state is correct. In addition, if the standard pressure change curve and threshold value are obtained in advance, when performing actual measurement, the target pressure change curve to be confirmed is acquired, and the already obtained standard pressure change curve and threshold value are used. The method of the invention can be carried out.
さて本発明では、基準の圧力変化曲線と吸引状態を確認する対象の圧力変化曲線とを比較するときに、吸引経過時間に依存する補正係数を使用する。この吸引経過時間に依存する補正係数は、吸引管内部の圧力に及ぼす試料粘度等の影響が吸引経過時間に依存すると仮定したことを反映している。たとえば、基準とする吸引状態が水等の粘度の低い液体を対象とし、吸引状態を確認する対象が血清等の粘度の高い液体であるとき、上記の補正係数はつぎのような形になる。基準とする吸引状態における圧力データｙｉをｙｃｉに変換するための補正係数は、観測する吸引経過時間の区間において単調増加であればよく、たとえば吸引経過時間に対する１次関数、２次関数およびそれ以上の高次関数であってよい。他方、確認する対象の吸引状態における圧力データＹｉをＹｃｉに変換するための補正係数は、観測する吸引経過時間の区間において単調減少であればよく、吸引経過時間に対する関数の形は、基準とする吸引状態における圧力データｙｉをｙｃｉに変換するための補正係数と同様で差し支えない。基準とする吸引状態の圧力データを変換して得たｙｃｉとＹｉとを比較することと、確認する対象の吸引状態の圧力データを変換して得たＹｃｉをｙｉとを比較することとは数学的に同値であり、一方を説明することが同時に他方を説明することになる。要するに、基準とする吸引状態と確認する対象の吸引状態とは、液体の粘度等の違いによる吸引管内の圧力への影響の度合いが異なるのだから、粘度等の影響を考慮して比較しようということである。 In the present invention, when comparing the reference pressure change curve with the pressure change curve of the object whose suction state is to be confirmed, a correction coefficient depending on the suction elapsed time is used. This correction coefficient that depends on the elapsed time of suction reflects the assumption that the influence of the sample viscosity and the like on the pressure inside the suction tube depends on the elapsed time of suction. For example, when the reference suction state is a liquid having a low viscosity such as water and the target whose suction state is to be confirmed is a liquid having a high viscosity such as serum, the above correction coefficient has the following form. The correction coefficient for converting the pressure data yi in the reference suction state to yci only needs to be monotonically increased in the section of the elapsed suction time to be observed. For example, a linear function, a quadratic function, or more with respect to the elapsed suction time It may be a higher order function. On the other hand, the correction coefficient for converting the pressure data Yi in the suction state of the target to be confirmed to Yci only needs to be monotonically decreased in the section of the elapsed suction time to be observed, and the form of the function with respect to the elapsed suction time is used as a reference. It may be the same as the correction coefficient for converting the pressure data yi in the suction state into yci. Comparing yci obtained by converting pressure data of a suction state as a reference and Yi and comparing Yci obtained by converting pressure data of a suction state to be confirmed with yi are mathematical Therefore, explaining one of them will explain the other at the same time. In short, the reference suction state and the target suction state to be confirmed differ in the degree of influence on the pressure in the suction pipe due to the difference in the viscosity of the liquid, etc. It is.
残差２乗和の最小値または残差２乗和の最小値の平方根によって異常吸引を総合的に検知するために、判断の基準となる閾値を利用する。閾値の設定のためには異常吸引が起こる状況を作り出してその圧力変化曲線を取得し、上述した残差２乗和の最小値またはその平方根を求めておく。たとえば、種々の濃度の血清アルブミンを水や血清に溶かして溶液の粘性を変えた試料を用意し、吸引に伴う圧力変化曲線を求めることにより、正常吸引がおこなわれる限界を求めておくのも好適である。また、吸引プローブの詰まりが起こりやすい種々の血液試料を用いて、異常吸引のいろいろな圧力変化パターンを採取し、閾値の設定に役立てることができる。正常吸引がおこなわれたかどうかは、同じ吸引試料の分析値の再現性を前提にして判断することもできるし、吸引サンプルの重量を直接測定することによっても確認できる。閾値の設定は、基準とする吸引状態の圧力データを取得したときと同様に吸引状態を大きく変える因子たとえば吸引量ごとにおこなうのが実際的である。 In order to detect abnormal suction comprehensively based on the minimum value of the residual sum of squares or the square root of the minimum value of the residual sum of squares, a threshold value serving as a criterion for determination is used. In order to set the threshold value, a situation in which abnormal suction occurs is created, its pressure change curve is acquired, and the minimum value or the square root of the above-mentioned residual sum of squares is obtained. For example, it is also preferable to determine the limit at which normal suction is performed by preparing samples with various concentrations of serum albumin dissolved in water or serum and changing the viscosity of the solution, and determining the pressure change curve accompanying suction. It is. Moreover, various pressure change patterns of abnormal suction can be collected using various blood samples that are likely to clog the suction probe, and can be used for setting a threshold value. Whether normal suction has been performed can be determined on the premise of the reproducibility of the analysis value of the same suction sample, or can be confirmed by directly measuring the weight of the suction sample. It is practical to set the threshold value for each factor that greatly changes the suction state, for example, the amount of suction, in the same manner as when the pressure data of the suction state as a reference is acquired.
吸引経過時間に依存する補正係数について、とくに計算が簡単で効果的に好ましいのは、補正係数が吸引経過時間の１次関数ｂ＋ａ×ｔｉとして表される場合である。ここで、パラメータｂおよびａは観測するそれぞれの吸引経過時間ｔｉに対して残差２乗和Σ｛Ｙｉ−（ｂ＋ａ×ｔｉ）ｙｉ｝２またはΣ｛ｙｉ−（ｂ＋ａ×ｔｉ）Ｙｉ｝２が最小となる定数である。残差２乗和Σ｛Ｙｉ−（ｂ＋ａ×ｔｉ）ｙｉ｝２とΣ｛ｙｉ−（ｂ＋ａ×ｔｉ）Ｙｉ｝２とでパラメータａとｂの数値ないし符号は異なる。パラメータａは吸引経過時間すなわち粘度等の寄与を含み、パラメータｂは基準となる吸引状態と確認する対象の吸引状態の圧力値のレベルを調整する機能を含んでいる。 Regarding the correction coefficient depending on the suction elapsed time, the calculation is particularly simple and effectively preferable when the correction coefficient is expressed as a linear function b + a × ti of the suction elapsed time. Here, the parameters b and a are the residual sum of squares Σ {Yi− (b + a × ti) yi} 2 or Σ {yi− (b + a × ti) Yi} 2 for each suction elapsed time ti to be observed. This is the smallest constant. The numerical values or signs of the parameters a and b differ between the residual sum of squares Σ {Yi− (b + a × ti) yi} 2 and Σ {yi− (b + a × ti) Yi} 2 . The parameter a includes a contribution such as a suction elapsed time, that is, a viscosity, and the parameter b includes a function of adjusting the level of the pressure value in the suction state to be confirmed and the suction state to be confirmed.
観測を開始する吸引経過時間ｔ１は吸引開始後の任意の所定時刻であってよく、吸引開始と同時でもよいし、吸引動作の後半であってもよい。観測する最後の吸引経過時間ｔｎはｔ１のあとの任意の所定時刻であってよく、負圧源の作動を停止する前でも後でもよい。ただし基準とする吸引状態の圧力データを取得する吸引経過時間ｔｉと確認する対象の吸引状態の圧力データを取得する吸引経過時間ｔｉは同一である必要がある。また、粘度の高い試料を吸引するときは、負圧源の動作を停止したあとでも吸引管内の圧力が変化するため、ｔｎを負圧源の動作を停止したあとの所定時刻とすることが確実に異常吸引を検出するために有用でありうる。 The suction elapsed time t1 for starting observation may be an arbitrary predetermined time after the start of suction, may be the same as the start of suction, or may be the latter half of the suction operation. The last suction elapsed time tn to be observed may be an arbitrary predetermined time after t1, and may be before or after the operation of the negative pressure source is stopped. However, the suction elapsed time ti for acquiring the reference suction state pressure data and the suction elapsed time ti for acquiring the target suction state pressure data to be confirmed need to be the same. Also, when sucking a highly viscous sample, the pressure in the suction tube changes even after the operation of the negative pressure source is stopped, so it is certain that tn is set to a predetermined time after the operation of the negative pressure source is stopped. It may be useful for detecting abnormal suction.
吸引管内の圧力データを取得する吸引経過時間ｔｉ（ｉ＝１，２，・・・，ｎ）のｎ数について制限はなく、実施条件により適宜設定すればよい。ｎ数として最低３点、多くて１００点程度が好適であり、５〜１５の間で設定するのがとくに好ましい。また、圧力データの取得間隔としては、とくに限定されるものではなく、等時間間隔としてもよいし、実施条件により異常吸引を検知するのに有効な時間帯を密に取得するのも好適である。ただし吸引状態の確認を正確に行なうためには、負圧が大きく変動する区間全体の圧力データを観測する吸引経過時間の区間として取得することが好ましい。たとえば吸引直後のみの圧力データを取得しても吸引後半に生じた異常吸引は検知できないし、負圧源の動作を停止した後のみの圧力データを取得しても吸引前半に生じた異常吸引は検知するのが困難となるためである。 There is no limitation on the number of suction elapsed times ti (i = 1, 2,..., N) for acquiring pressure data in the suction pipe, and it may be set as appropriate according to the implementation conditions. The number of n is preferably at least 3 points and at most about 100 points, and is particularly preferably set between 5 and 15. Further, the pressure data acquisition interval is not particularly limited, and may be an equal time interval, or it is also preferable to acquire a time zone effective for detecting abnormal suction depending on the implementation conditions. . However, in order to confirm the suction state accurately, it is preferable to obtain the suction elapsed time section in which the pressure data of the entire section in which the negative pressure fluctuates greatly is observed. For example, even if pressure data just after suction is acquired, abnormal suction that occurs in the second half of suction cannot be detected, and even if pressure data is acquired only after the operation of the negative pressure source is stopped, abnormal suction that occurs in the first half of suction is not This is because it becomes difficult to detect.
基準とする吸引状態の圧力データを取得するためには、正常吸引がおこなわれるように、基準試料として水を使用するのが便利かつ好適である。一方、精密な異常吸引の検知のためには、基準試料として、吸引状態を確認する対象の試料と同じ種類の溶媒で、閉塞の原因となるものが取り除かれたものを使用するのが望ましい。同じ種類の溶媒とは、粘度や密度、表面張力等の圧力変化曲線に影響を与えると思われる物性が、吸引状態を確認する対象の試料と同様の値を示すように、確認する対象がたとえば血清であれば基準試料にも血清を使用することがあげられる。また、溶媒の物性の中でも主に粘度が圧力変化曲線に与える影響が大きいため、粘度が近い溶媒、たとえば吸引状態を確認する対象の試料が血清ならば、基準試料として、十分に管理された標準血清、コントロール血清あるいは血清アルブミン水溶液を使用するのが好ましい。また同様の物性の溶媒として、吸引状態を確認する対象の試料自体を使用してもよいが、この場合は基準とする吸引状態の圧力データを取得する際には確実に正常吸引を行なわせる必要があるため、閉塞の原因となるものを取り除いたり、複数回の実験から取得した圧力データの平均値を基準とする吸引状態の圧力データとすることが望ましい。 In order to acquire pressure data of a suction state as a reference, it is convenient and preferable to use water as a reference sample so that normal suction is performed. On the other hand, for precise detection of abnormal suction, it is desirable to use, as a reference sample, the same type of solvent as that of the sample whose suction state is to be confirmed, from which the cause of clogging has been removed. The same type of solvent means that the object to be checked is such that the physical properties that are thought to affect the pressure change curve such as viscosity, density, surface tension, etc. show the same values as the sample to be checked for suction. In the case of serum, serum can be used as a reference sample. In addition, among the physical properties of the solvent, the viscosity has a large influence on the pressure change curve. Therefore, if the solvent whose viscosity is close, for example, the sample to be checked for suction, is serum, a well-controlled standard as a reference sample It is preferred to use serum, control serum or serum albumin aqueous solution. In addition, as the solvent with the same physical properties, the sample itself for which the suction state is to be confirmed may be used. However, in this case, it is necessary to ensure that normal suction is performed when acquiring pressure data for the reference suction state. Therefore, it is desirable to remove the cause of the blockage or to set the pressure data in the suction state based on the average value of the pressure data acquired from a plurality of experiments.
負圧源としては各種吸引ポンプが使用できる。本発明の方法を分注装置のサンプリングプローブに適用することを想定すると、吸引・吐出動作の制御が容易なシリンジポンプを使用するのがとくに好適である。 Various suction pumps can be used as the negative pressure source. Assuming that the method of the present invention is applied to a sampling probe of a dispensing apparatus, it is particularly preferable to use a syringe pump that can easily control suction and discharge operations.
負圧源に接続された吸引管としては各種サンプリングプローブが使用できるが、サンプリングプローブの先端から直接液体を吸引してもよいし、ディスポーザブルチップを使用してもよい。また、吸引管と負圧源の接続は直接接続されていてもよいし、間にトラップ等を介して接続されていてもよい。 Various sampling probes can be used as the suction tube connected to the negative pressure source, but the liquid may be sucked directly from the tip of the sampling probe, or a disposable tip may be used. Further, the connection between the suction pipe and the negative pressure source may be directly connected, or may be connected via a trap or the like therebetween.
本発明によれば、正常な吸引がおこなわれた圧力変化曲線と、試料を吸引したときの圧力変化曲線との相似性により吸引状態を総合的に評価するに際して、吸引経過時間に依存する補正係数によって、吸引管内部の圧力に及ぼす試料粘度等の影響を効果的に抑制して、正確な評価を実施することができる。たとえば、粘度が高い液体を異常吸引と判定する誤りを防止することができる。また、正常吸引と異常吸引との区別の精度を高め、閾値の設定における信頼性を高めることができる。本発明では、正常な吸引がおこなわれた圧力変化曲線と、試料を吸引したときの圧力変化曲線とを統計的に当てはめ、その残差２乗和の最小値またはその残差２乗和の最小値の平方根を吸引状態の指標とするので、直感的には両曲線の形を比較することになる。したがって、基準とする吸引状態および個々の確認する対象の吸引状態における圧力値のレベルそのものに対する高い再現性は要求されない。すなわち、基準の圧力変化曲線の取得時と確認する対象の圧力変化曲線の取得時とにおける圧力センサの精密なゲイン調節が不要である。したがって本発明は、吸引中または吸引停止後のある時点における圧力を閾値と比較する従来法に比べて、より安定性の高い方法であると言える。 According to the present invention, when comprehensively evaluating the suction state based on the similarity between the pressure change curve in which normal suction is performed and the pressure change curve when the sample is sucked, a correction coefficient that depends on the elapsed time of suction. Thus, it is possible to effectively suppress the influence of the sample viscosity and the like on the pressure inside the suction tube, and to perform accurate evaluation. For example, an error in determining a liquid having a high viscosity as abnormal suction can be prevented. Further, the accuracy of distinguishing between normal suction and abnormal suction can be increased, and the reliability in setting the threshold can be increased. In the present invention, the pressure change curve in which normal suction is performed and the pressure change curve when the sample is sucked are statistically applied, and the minimum value of the residual square sum or the minimum of the residual square sum is obtained. Since the square root of the value is used as an index of the suction state, the shapes of both curves are intuitively compared. Therefore, high reproducibility with respect to the pressure value level itself in the reference suction state and the suction state of each object to be confirmed is not required. That is, it is not necessary to precisely adjust the gain of the pressure sensor when acquiring the reference pressure change curve and when acquiring the target pressure change curve. Therefore, the present invention can be said to be a more stable method than the conventional method in which the pressure at a certain point in time during or after the suction is stopped is compared with a threshold value.
さらに本発明の方法は、生化学自動分析装置などに搭載される試料の自動吸引手段における吸引状態を確認する方法として実施することも可能である。この場合には、たとえば生化学自動分析装置の記憶手段などに予め取得した基準の圧力変化曲線および閾値を記憶しておき、センサーで測定した確認する対象の圧力変化曲線を演算装置に出力し、自動的に吸引状態の正否をディスプレイやプリンタ等の表示手段に表示することが可能となる。 Furthermore, the method of the present invention can also be implemented as a method for confirming the suction state in an automatic sample suction means mounted on a biochemical automatic analyzer or the like. In this case, for example, a reference pressure change curve and a threshold value acquired in advance in the storage means of the biochemical automatic analyzer, for example, are stored, and the pressure change curve to be confirmed measured by the sensor is output to the arithmetic unit. It is possible to automatically display whether the suction state is correct or not on a display means such as a display or a printer.
確認する対象の吸引状態における圧力データＹｉと、基準とする吸引状態における圧力データｙｉを補正係数ｂ＋ａ×ｔｉによって変換して得たｙｃｉとから、残差２乗和Σ（Ｙｉ−ｙｃｉ）２すなわちΣ｛Ｙｉ−（ｂ＋ａ×ｔｉ）ｙｉ｝２の最小値を求め、その平方根を吸引状態の正否を確認する指標とする場合を例にとり、本発明を実施するための最良の形態を説明する。 From the pressure data Yi in the suction state to be checked and the yci obtained by converting the pressure data yi in the reference suction state by the correction coefficient b + a × ti, the residual sum of squares Σ (Yi−yci) 2 , The best mode for carrying out the present invention will be described by taking as an example the case where the minimum value of Σ {Yi− (b + a × ti) yi} 2 is obtained and the square root is used as an index for confirming the correctness of the suction state.
残差２乗和Σ｛Ｙｉ−（ｂ＋ａ×ｔｉ）ｙｉ｝２が最小となるパラメータａとｂを求めるため、ｂとａに関する偏導関数をそれぞれ０とおいてつぎの方程式（１）、（２）を得る：
∂Σ｛Ｙｉ−（ｂ＋ａ×ｔｉ）ｙｉ｝２／∂ａ ＝ −ΣＹｉｙｉｔｉ＋ｂΣｙｉ２ｔｉ＋ａΣｙｉ２ｔｉ２＝０・・・・・（１）
∂Σ｛Ｙｉ−（ｂ＋ａ×ｔｉ）ｙｉ｝２／∂ｂ ＝ −ΣＹｉｙｉ＋ｂΣｙｉ２＋ａΣｙｉ２ｔｉ＝０・・・・・（２）
式（１）、（２）よりパラメータａおよびｂを求める次式を得る：
ａ＝(ΣＹｉｙｉ×Σｙｉ２ｔｉ−Σｙｉ２×ΣＹｉｙｉｔｉ)／｛(Σｙｉ２ｔｉ）２−Σｙｉ２×Σｙｉ２ｔｉ２｝・・・・・（３）
ｂ＝(ΣＹｉｙｉ−ａΣｙｉ２ｔｉ）／Σｙｉ２・・・・・（４）
確認する対象の吸引状態における圧力データＹｉと、基準とする吸引状態における圧力データｙｉを式（３）、（４）に代入してａおよびｂの数値を求める。こうして求めたａおよびｂの数値を用いて、個々の実測した圧力データＹｉと、基準とする吸引状態における圧力データｙｉとから、残差２乗和Σ｛Ｙｉ−（ｂ＋ａ×ｔｉ）ｙｉ｝２を算出する。この残差２乗和の最小値の正の平方根を閾値に対して比較する。
In order to obtain the parameters a and b that minimize the residual sum of squares Σ {Yi− (b + a × ti) yi} 2, the partial derivatives relating to b and a are set to 0, and the following equations (1) and (2 Get):
∂Σ {Yi− (b + a × ti) yi} 2 / ∂a = −ΣYiiti + bΣyi 2 ti + aΣyi 2 ti 2 = 0 (1)
∂Σ {Yi− (b + a × ti) yi} 2 / ∂b = −ΣYii + bΣyi 2 + aΣyi 2 ti = 0 (2)
From the equations (1) and (2), the following equation for obtaining the parameters a and b is obtained:
a = (ΣYiii × Σyi 2 ti−Σyi 2 × ΣYiiti) / {(Σyi 2 ti) 2 −Σyi 2 × Σyi 2 ti 2 } (3)
b = (ΣYiii−aΣyi 2 ti) / Σyi 2 (4)
The pressure data Yi in the suction state to be confirmed and the pressure data yi in the reference suction state are substituted into formulas (3) and (4) to obtain numerical values of a and b. Using the numerical values of a and b thus obtained, the residual square sum Σ {Yi− (b + a × ti) yi} 2 from each actually measured pressure data Yi and the pressure data yi in the reference suction state. Is calculated. The positive square root of the minimum value of the residual sum of squares is compared against a threshold value.
実施例１
本発明の方法を実施するための最良の形態の適用例として、正常吸引、詰まりの傾向および空吸いの現象について順次述べる。圧力データの値は吸引前の圧力を０としたときの負圧（任意単位）で示した。
Example 1
As an application example of the best mode for carrying out the method of the present invention, normal suction, clogging tendency, and idling phenomenon will be sequentially described. The value of the pressure data is shown as negative pressure (arbitrary unit) when the pressure before suction is 0.
図１は、基準とする正常な吸引状態を表す圧力データと、検体の吸引状態を表す圧力データとが、吸引経過時間に対してほぼ同様に推移する正常吸引の例である。シリンジポンプに接続された吸引管の先端に使い捨てピペットチップを装着した。吸引管内部の空気の圧力を測定する圧力センサの出力をモニターした。開口容器中の水吸引を５回繰り返して得た圧力データの平均値を、基準とする吸引状態における圧力データとした。確認する対象として血清検体を吸引した。吸引量は１回あたり１００μＬ、シリンジポンプの動作時間は約５５０ｍｓである。吸引開始後約１００ｍｓの時点での圧力データをとり、吸引動作中に８点、吸引動作停止後２００ｍｓの圧力データまであわせて９点の圧力データをプロットした。図１において基準とする吸引状態の圧力データ（黒丸のプロットマーカー）および、実測した血清の吸引に伴う圧力データ（白四角のプロットマーカー）をそれぞれ折れ線で結んだ。これらの圧力−時間データを上の式（３）、（４）に代入して、パラメータａ，ｂを求め、基準となる圧力データに補正係数ｂ＋ａ×ｔｉ（この例ではｂ＝１．０、ａ＝０．２）を掛けて補正した圧力データｙｃｉの変化を破線で示した。図１が示しているように、補正した圧力データは実測した血清の吸引状態を表すプロットとほとんど重なっている。この正常吸引の例の場合、残差２乗和の最小値の正の平方根は３．３（負圧を表す任意単位）であった。 FIG. 1 is an example of normal suction in which pressure data representing a normal suction state as a reference and pressure data representing a specimen suction state change in substantially the same manner with respect to the elapsed suction time. A disposable pipette tip was attached to the tip of the suction tube connected to the syringe pump. The output of a pressure sensor that measures the pressure of air inside the suction pipe was monitored. The average value of the pressure data obtained by repeating the water suction in the open container five times was used as the pressure data in the suction state as a reference. Serum specimens were aspirated as subjects to be confirmed. The suction amount is 100 μL per one time, and the operation time of the syringe pump is about 550 ms. The pressure data at a time point of about 100 ms after the start of suction was taken, and 9 points of pressure data were plotted, including 8 points during the suction operation and 200 ms after the suction operation was stopped. In FIG. 1, the pressure data (black circle plot marker) in the suction state as a reference and the pressure data (white square plot marker) associated with the actually measured serum suction are connected by broken lines. By substituting these pressure-time data into the above equations (3) and (4), parameters a and b are obtained, and the correction data b + a × ti (in this example, b = 1.0, The change in the pressure data yci corrected by multiplying by a = 0.2) is shown by a broken line. As shown in FIG. 1, the corrected pressure data almost overlaps with the plot representing the actually measured serum aspiration state. In the case of this normal suction, the positive square root of the minimum value of the residual sum of squares was 3.3 (arbitrary unit representing negative pressure).
図２は、血清の吸引に伴う負圧の上昇（減圧の進行）が顕著な、詰まりの傾向を示す異常吸引の例である。基準となる圧力データ、吸引量、圧力データの取得時間等の実験条件は図１と同じである。今度は図１と異なり、４００ｍｓ手前から吸引動作が停止する直前である約５５０ｍｓまで負圧が高く維持されている。しかし、吸引動作停止後２００ｍｓの時点で血清吸引の負圧レベルは基準の圧力データとほぼ同じレベルまで下がっている。これは、たとえばゆるく架橋したフィブリン凝固体のようなものがピペット先端の狭窄部で停滞したのち、吸引圧に負けて吸い込まれた結果とも考えられる。このような状態で吸引採取した試料は分析に悪影響を与える要因を有していると見なければならない。吸引動作停止後の所定時期の圧力を指標として異常吸引を検知する従来の方法では、この例のような不完全な詰まり現象を検知することはできなかった。図２のデータにおいて補正のパラメータは、ｂ＝０．５、ａ＝２．１であり、残差２乗和の最小値の正の平方根は４２．７であった。この値４２．７は異常吸引を強く示唆している。 FIG. 2 is an example of abnormal suction showing a tendency of clogging, in which the increase in negative pressure accompanying the suction of serum (progress of pressure reduction) is remarkable. The experimental conditions such as the reference pressure data, the suction amount, and the acquisition time of the pressure data are the same as those in FIG. This time, unlike FIG. 1, the negative pressure is kept high from 400 ms before to about 550 ms, which is just before the suction operation stops. However, at 200 ms after stopping the suction operation, the negative pressure level of the serum suction has dropped to almost the same level as the reference pressure data. This is also considered to be a result of, for example, a loosely cross-linked fibrin solidified body stagnating at the narrowed portion at the tip of the pipette and then sucked in against the suction pressure. The sample collected by suction in such a state must be regarded as having a factor that adversely affects the analysis. The conventional method of detecting abnormal suction using the pressure at a predetermined time after stopping the suction operation as an index cannot detect the incomplete clogging phenomenon as in this example. In the data of FIG. 2, the correction parameters were b = 0.5 and a = 2.1, and the positive square root of the minimum value of the residual sum of squares was 42.7. This value 42.7 strongly suggests abnormal suction.
図３は、吸引中に負圧が異常低下を示した、空吸いの傾向を示す異常吸引の例である。基準となる圧力データ、吸引量、圧力データの取得時間等の実験条件は図１、２と同じである。血清検体の実測データにおいて、３００ｍｓを過ぎたあたりから負圧の急激な低下が起こっている。これは液面検知の過誤あるいは気泡の存在により、吸引中に検体が不足して空吸いが起きたことが考えられる。このデータにおいて、補正のパラメータは、ｂ＝１．５、ａ＝−２．０であり、残差２乗和の最小値の正の平方根は３０．７であった。この例もまた、吸引動作停止後の所定時期の圧力を指標とする従来の方法では検知できなかった異常吸引を本発明の方法が検知できることを示している。 FIG. 3 is an example of abnormal suction showing a tendency of idle suction, in which the negative pressure shows an abnormal drop during suction. Experimental conditions such as reference pressure data, suction amount, and pressure data acquisition time are the same as in FIGS. In the actual measurement data of the serum sample, the negative pressure has suddenly decreased after about 300 ms. This is probably because the sample was insufficient during aspiration due to an error in detecting the liquid level or the presence of bubbles. In this data, the correction parameters were b = 1.5 and a = −2.0, and the positive square root of the minimum value of the residual sum of squares was 30.7. This example also shows that the method of the present invention can detect abnormal suction that could not be detected by the conventional method using the pressure at a predetermined time after stopping the suction operation as an index.
以上の結果から、この測定系においては閾値を１０程度に設定することで、詰まりや空吸いの異常吸引を検知し、吸引状態の正否を確認することができた。 From the above results, by setting the threshold value to about 10 in this measurement system, it was possible to detect clogging or abnormal suction due to idle suction, and to confirm the correctness of the suction state.
実施例２
本発明の特徴の一つは、吸引管内部の圧力に及ぼす試料粘度の影響を考慮するために、吸引経過時間に依存する補正係数を用いて、基準の圧力変化曲線と検査対象の圧力変化曲線とを比較することである。すなわち、補正係数としてｂ＋ａ×ｔｉを使うのであればパラメータａが重要な役割を果たしている。このことを実例により説明する。
Example 2
One of the features of the present invention is that, in order to consider the influence of the sample viscosity on the pressure inside the suction tube, a correction coefficient depending on the elapsed time of suction is used, and the reference pressure change curve and the pressure change curve of the inspection object are used. Is to compare. That is, if b + a × ti is used as a correction coefficient, the parameter a plays an important role. This will be explained with an example.
仮に補正係数の時間依存性を考慮しない場合、すなわち補正係数ｂ＋ａ×ｔｉのパラメータａが０のとき、式（４）によりｂ＝ΣＹｉｙｉ／Σｙｉ２となる。取得した圧力データをこの式に代入してｂの数値を求める。こうして求めたｂの数値を用いて、個々の実測した圧力データＹｉと、基準とする吸引状態における圧力データｙｉとから、残差２乗和Σ（Ｙｉ−ｂ×ｙｉ）２を算出する。この残差２乗和の正の平方根を本発明による残差２乗和Σ｛Ｙｉ−（ｂ＋ａ×ｔｉ）ｙｉ｝２の正の平方根と比較した。 If the time dependency of the correction coefficient is not taken into consideration, that is, when the parameter a of the correction coefficient b + a × ti is 0, b = ΣYiii / Σyi 2 according to the equation (4). Substituting the acquired pressure data into this equation, the numerical value of b is obtained. The residual sum of squares Σ (Yi−b × yi) 2 is calculated from each actually measured pressure data Yi and the pressure data yi in the reference suction state by using the numerical value of b thus obtained. The positive square root of the residual square sum was compared with the positive square root of the residual square sum Σ {Yi− (b + a × ti) yi} 2 according to the present invention.
説明のために図４にヒト血清検体に対する圧力変化曲線の一例を示す。基準となる圧力変化曲線、吸引量、圧力データの取得時間等の実験条件は図１〜３と同じである。図４において基準とする吸引状態の圧力データ（黒丸のプロットマーカー）および、実測した血清の吸引に伴う圧力データ（白四角のプロットマーカー）をそれぞれ折れ線で結んだ。これらの圧力−時間データを上の式（３）、（４）に代入して、パラメータａ，ｂを求め、基準となる圧力データに補正係数ｂ＋ａ×ｔｉ（この例ではｂ＝１．１４、ａ＝１．９４）を掛けて補正した圧力データｙｃｉの変化を破線で示した（補正（ａ，ｂ））。他方、同じ圧力−時間データをｂ＝ΣＹｉｙｉ／Σｙｉ２に代入して、パラメータｂを求め、基準となる圧力データに補正係数ｂ（この例ではｂ＝１．７５）を掛けて補正した圧力データｙｃｉの変化を一点鎖線で示した（補正（ａ＝０））。 For illustration, FIG. 4 shows an example of a pressure change curve for a human serum sample. Experimental conditions such as a pressure change curve, suction amount, and pressure data acquisition time are the same as in FIGS. In FIG. 4, the pressure data of the suction state as a reference (black circle plot marker) and the pressure data (white square plot marker) associated with the actually measured serum are connected by a broken line. By substituting these pressure-time data into the above equations (3) and (4), parameters a and b are obtained, and the correction data b + a × ti (in this example, b = 1.14, The change of the pressure data yci corrected by multiplying by a = 1.94) is indicated by a broken line (correction (a, b)). On the other hand, by substituting the same pressure-time data into b = ΣYiii / Σyi 2 to obtain parameter b, pressure data corrected by multiplying the reference pressure data by a correction coefficient b (in this example, b = 1.75). The change in yci is indicated by a one-dot chain line (correction (a = 0)).
実測した血清の圧力変化曲線（白四角のプロットマーカー）の形状を見ると、図２に見られるような吸引後半５５０ｍｓ付近の負圧のふくらみや、図３に見られるような吸引途中における負圧の急激な落ち込みも見られない。また、吸引動作停止後の圧力も基準の圧力変化曲線とほぼ同じレベルにまで下がっている。さらに、この吸引操作後の血清の分析値に異常の報告がなされていないことからも、図４に示した血清の吸引に異常性は認められない。図４を詳細に観察すると、基準の圧力変化曲線のピーク位置（時間軸）に比べて、実測した圧力変化曲線のピーク位置はやや右側にシフトしていることがわかる。パラメータａを０とした補正による圧力変化曲線（一点鎖線）は基準の圧力変化曲線を上方に比例的に移動させた形となっているのに対して、補正係数ｂ＋ａ×ｔｉを使用する本願の方法による圧力変化曲線（破線）は、実測した圧力変化曲線の時間方向にシフトしたピークによく追随していることがわかる。じっさい、補正係数ｂ＋ａ×ｔｉを用いる本発明による残差２乗和の正の平方根は８．２であるのに対して、ａ＝０とした補正、すなわち吸引経過時間に依存しない補正係数により補正した残差２乗和の正の平方根は４４．１であった。 Looking at the shape of the actually measured serum pressure change curve (white square plot marker), the negative pressure bulge in the vicinity of 550 ms in the latter half of the suction as shown in FIG. 2 and the negative pressure during the suction as shown in FIG. There is no sudden drop in the price. In addition, the pressure after stopping the suction operation is also reduced to almost the same level as the reference pressure change curve. Furthermore, since there is no report of an abnormality in the serum analysis value after the suction operation, no abnormality is found in the serum suction shown in FIG. When FIG. 4 is observed in detail, it can be seen that the peak position of the actually measured pressure change curve is slightly shifted to the right as compared with the peak position (time axis) of the reference pressure change curve. The pressure change curve (one-dot chain line) by correction with the parameter a set to 0 has a shape in which the reference pressure change curve is proportionally moved upward, whereas the correction coefficient b + a × ti is used. It can be seen that the pressure change curve (broken line) by the method well follows the peak shifted in the time direction of the actually measured pressure change curve. In fact, the positive square root of the residual sum of squares according to the present invention using the correction coefficient b + a × ti is 8.2, whereas the correction is made with a = 0, that is, the correction coefficient independent of the suction elapsed time. The positive square root of the residual sum of squares was 44.1.
したがって、補正係数に時間依存性を考慮しない場合には正常吸引であっても残差２乗和Σ｛Ｙｉ−（ｂ＋ａ×ｔｉ）ｙｉ｝２の正の平方根が高い値を示してしまうため、実施例１のように閾値を１０程度に設定すると、異常吸引と正常吸引の区別をすることができないことがわかった。 図４に示したデータを含み、異常吸引が報告されていない２４４個の吸引測定データを図５にまとめた。吸引検体はヒト血清である。図５には、本発明による補正係数ｂ＋ａ×ｔｉを用いたときの残差２乗和の正の平方根（補正（ａ，ｂ））と、パラメータａ＝０としたときの残差２乗和の正の平方根（補正（ａ＝０））とに関する度数分布を折れ線で示した。階級の幅は、残差２乗和の正の平方根について０．５（負圧：任意単位）とした。本発明による方法（補正（ａ，ｂ））で算出した残差２乗和の正の平方根の分布は、あきらかに正常な吸引状態を反映するデータにおける平均値が３．５、標準偏差が０．８の正規分布に近い形状を示している。これに対してパラメータａ＝０としたときの分布（補正（ａ＝０））は、残差２乗和の正の平方根が１４以上のデータを除く平均値が５．４、標準偏差が１．７で、右側に広がるブロードな分布を示している。とくに、残差２乗和の正の平方根が１５を超えるデータ３点の内訳は、本願による補正（ａ，ｂ）と補正（ａ＝０）の組として、それぞれ｛８．２， ４４．１｝、｛１１．４， ５７．８｝および｛１１．１， ２７．４｝となっており、本願方法は正常吸引を異常吸引と判定する誤りを回避することに役立つことがわかる。 Therefore, when the time dependency is not considered in the correction coefficient, the positive square root of the residual sum of squares Σ {Yi− (b + a × ti) yi} 2 shows a high value even in normal suction. It was found that when the threshold was set to about 10 as in Example 1, it was impossible to distinguish between abnormal suction and normal suction. FIG. 5 summarizes 244 suction measurement data including the data shown in FIG. 4 and no reported abnormal suction. The aspirated specimen is human serum. FIG. 5 shows the positive square root (correction (a, b)) of the residual sum of squares when the correction coefficient b + a × ti according to the present invention is used, and the residual sum of squares when the parameter a = 0. The frequency distribution with respect to the positive square root (correction (a = 0)) is indicated by a broken line. The width of the class was 0.5 (negative pressure: arbitrary unit) for the positive square root of the residual sum of squares. The distribution of the positive square root of the residual sum of squares calculated by the method according to the present invention (correction (a, b)) clearly has an average value of 3.5 and a standard deviation of 0 in data reflecting a normal suction state. A shape close to a normal distribution of .8 is shown. On the other hand, the distribution (correction (a = 0)) when the parameter a = 0 is set, the average value excluding the data whose positive square root of the residual sum of squares is 14 or more is 5.4, and the standard deviation is 1. .7 shows a broad distribution spreading to the right. In particular, the breakdown of the three data points whose positive square root of the residual sum of squares exceeds 15 is {8.2, 44.1, respectively, as a combination of correction (a, b) and correction (a = 0) according to the present application. }, {11.4, 57.8} and {11.1, 27.4}, it can be seen that the present method is useful for avoiding an error in determining normal suction as abnormal suction.
Claims (5)
・基準とする吸引状態において吸引経過時間ｔｉ（ｉ＝１，２，・・・，ｎ）に対して前記吸引管内部の圧力データｙｉ（ｉ＝１，２，・・・，ｎ）を取得することと、
・確認する対象の吸引状態において吸引経過時間ｔｉ（ｉ＝１，２，・・・，ｎ）に対して前記吸引管内部の圧力データＹｉ（ｉ＝１，２，・・・，ｎ）を取得することと、
・前記圧力データｙｉを吸引経過時間に依存する補正係数によって変換した圧力データｙｃｉ（ｉ＝１，２，・・・，ｎ）または前記圧力データＹｉを吸引経過時間に依存する補正係数によって変換した圧力データＹｃｉ（ｉ＝１，２，・・・，ｎ）を得ることと、
・ＹｉとｙｃｉとからまたはｙｉとＹｃｉとから、残差２乗和Σ（Ｙｉ−ｙｃｉ）２の最小値またはΣ（ｙｉ−Ｙｃｉ）２の最小値を算出することと、
・算出された残差２乗和の最小値または算出された残差２乗和の最小値の平方根を閾値に対して比較することと、
・この比較結果に応じて吸引状態の正否を確認することと、を含む前記方法。 A method for confirming a suction state when a predetermined amount of liquid is sucked through a tip of a suction pipe connected to a negative pressure source,
・ Acquires pressure data yi (i = 1, 2,..., N) inside the suction pipe with respect to the suction elapsed time ti (i = 1, 2,..., N) in the reference suction state. To do
The pressure data Yi (i = 1, 2,..., N) inside the suction pipe with respect to the suction elapsed time ti (i = 1, 2,..., N) in the suction state to be confirmed. Getting,
The pressure data yci (i = 1, 2,..., N) converted from the pressure data yi by a correction coefficient depending on the suction elapsed time or the pressure data Yi was converted by a correction coefficient depending on the suction elapsed time. Obtaining pressure data Yci (i = 1, 2,..., N);
Calculating the minimum value of the residual sum of squares Σ (Yi−yci) 2 or the minimum value of Σ (yi−Yci) 2 from Yi and yci or from yi and Yci;
Comparing the minimum value of the calculated residual sum of squares or the square root of the minimum value of the calculated residual sum of squares against a threshold;
-Checking the correctness of the suction state according to the comparison result, the method.
The method according to any one of claims 1 to 3, wherein, in a reference suction state, the same kind of solvent as that of the sample whose suction state is to be confirmed is sucked.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005125756A JP4524642B2 (en) | 2005-04-22 | 2005-04-22 | How to check the suction status |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005125756A JP4524642B2 (en) | 2005-04-22 | 2005-04-22 | How to check the suction status |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2006300843A true JP2006300843A (en) | 2006-11-02 |
| JP4524642B2 JP4524642B2 (en) | 2010-08-18 |
Family
ID=37469294
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2005125756A Expired - Fee Related JP4524642B2 (en) | 2005-04-22 | 2005-04-22 | How to check the suction status |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4524642B2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011505561A (en) * | 2007-11-30 | 2011-02-24 | シーメンス・ヘルスケア・ダイアグノスティックス・インコーポレーテッド | Insufficient sample detection during pipetting |
| JP2013053868A (en) * | 2011-09-01 | 2013-03-21 | Hitachi High-Technologies Corp | Automatic analyzer |
| WO2013161300A1 (en) * | 2012-04-24 | 2013-10-31 | 株式会社マイクロジェット | Discharge system and method for discharging by discharge system |
| CN112858593A (en) * | 2021-02-22 | 2021-05-28 | 广州科方生物技术股份有限公司 | Detection system and detection method for sample needle, reagent needle suction and needle blockage |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03145549A (en) * | 1989-10-30 | 1991-06-20 | Japan Electron Control Syst Co Ltd | Intake flow measuring device for internal combustion engine |
| JP2001165934A (en) * | 1999-12-06 | 2001-06-22 | Toshiba Corp | Automatic analyzer and automatic analysis system |
| JP2004125780A (en) * | 2002-08-07 | 2004-04-22 | Hitachi High-Technologies Corp | Sample dispensing apparatus and automatic analyzer using it |
| JP2004177308A (en) * | 2002-11-28 | 2004-06-24 | Toshiba Medical System Co Ltd | Method for judging attraction state and automatic chemical analyzer |
-
2005
- 2005-04-22 JP JP2005125756A patent/JP4524642B2/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03145549A (en) * | 1989-10-30 | 1991-06-20 | Japan Electron Control Syst Co Ltd | Intake flow measuring device for internal combustion engine |
| JP2001165934A (en) * | 1999-12-06 | 2001-06-22 | Toshiba Corp | Automatic analyzer and automatic analysis system |
| JP2004125780A (en) * | 2002-08-07 | 2004-04-22 | Hitachi High-Technologies Corp | Sample dispensing apparatus and automatic analyzer using it |
| JP2004177308A (en) * | 2002-11-28 | 2004-06-24 | Toshiba Medical System Co Ltd | Method for judging attraction state and automatic chemical analyzer |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011505561A (en) * | 2007-11-30 | 2011-02-24 | シーメンス・ヘルスケア・ダイアグノスティックス・インコーポレーテッド | Insufficient sample detection during pipetting |
| EP2217905A4 (en) * | 2007-11-30 | 2017-12-20 | Siemens Healthcare Diagnostics Inc. | Detection of insufficient sample during aspiration with a pipette |
| JP2013053868A (en) * | 2011-09-01 | 2013-03-21 | Hitachi High-Technologies Corp | Automatic analyzer |
| WO2013161300A1 (en) * | 2012-04-24 | 2013-10-31 | 株式会社マイクロジェット | Discharge system and method for discharging by discharge system |
| CN104246514A (en) * | 2012-04-24 | 2014-12-24 | 小滴喷射有限公司 | Injection system and method for injection using an injection system |
| JPWO2013161300A1 (en) * | 2012-04-24 | 2015-12-24 | 株式会社マイクロジェット | Discharge system and method of discharging by discharge system |
| CN104246514B (en) * | 2012-04-24 | 2016-08-17 | 小滴喷射有限公司 | Injection system and method for injection using an injection system |
| US9555431B2 (en) | 2012-04-24 | 2017-01-31 | Microjet Corporation | Discharge system and method of discharge by a discharge system |
| CN112858593A (en) * | 2021-02-22 | 2021-05-28 | 广州科方生物技术股份有限公司 | Detection system and detection method for sample needle, reagent needle suction and needle blockage |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4524642B2 (en) | 2010-08-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7694591B2 (en) | Method and apparatus for evaluating a dosing operation | |
| US7477997B2 (en) | Method for ascertaining interferants in small liquid samples in an automated clinical analyzer | |
| JP5123390B2 (en) | Detection of clogging in clinical sampling pipettes | |
| US9523677B2 (en) | System and method of verification of a prepared sample for a flow cytometer | |
| EP2217905B1 (en) | Detection of insufficient sample during aspiration with a pipette | |
| US10288637B2 (en) | Automatic analyzer | |
| US20090266149A1 (en) | Differentiating Between Abnormal Sample Viscosities and Pipette Clogging During Aspiration | |
| EP2952902B1 (en) | Automated analysis device | |
| JP2001021572A (en) | Method for confirming aspirated volume of fluid | |
| JP6407895B2 (en) | Automatic analyzer | |
| US20110061471A1 (en) | System and method of verification of a sample for a flow cytometer | |
| JP6009148B2 (en) | Method for estimating viscosity | |
| JP4524642B2 (en) | How to check the suction status | |
| US7634367B1 (en) | Estimating fluidic properties and using them to improve the precision/accuracy of metered fluids and to improve the sensitivity/specificity in detecting failure modes | |
| WO2017108647A1 (en) | Method of detecting the presence or absence of a clot in a liquid sample analyzer | |
| EP2302397A1 (en) | Method, computer program, and apparatus for detecting pipetting errors | |
| JP2013044530A (en) | Dispenser | |
| JP2005055446A (en) | Method of detecting gas bubbles in liquid | |
| US7779666B2 (en) | Method for checking the condition of a sample when metering liquid | |
| JPH02196963A (en) | Detection of short sample of automatic dispenser | |
| JP2005164293A (en) | Dispensing device | |
| JPH06180272A (en) | Measuring method for liquid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20080312 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20100112 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100216 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20100506 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100519 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130611 Year of fee payment: 3 |
|
| R151 | Written notification of patent or utility model registration |
Ref document number: 4524642 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R151 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130611 Year of fee payment: 3 |
|
| LAPS | Cancellation because of no payment of annual fees |