Method for measuring the plasma concentration of an analyte directly on a whole blood sample

• US 10,132,800 B2
• Filed: 05/12/2014
• Issued: 11/20/2018
• Est. Priority Date: 05/13/2013
• Status: Active Grant

• Current Assignee: Biomerieux B.V. (Compagnie Merieux Alliance SAS)
• Original Assignee: Biomerieux B.V. (Compagnie Merieux Alliance SAS)
• Inventors: Cheucle, Sylvie, Marillet, Laure, Thollet, Aurelie
• Primary Examiner(s): Dejong, Eric S
• Application Number:
  US14/787,790
• Publication Number:
  US 20160116463A1
• Time in Patent Office: 1,653 Days
• Field of Search: None
• CPC Class Codes: G01N 2333/47 Assays involving proteins of known structure or function as defined in the subgroups
• CPC Class Codes: G01N 2333/4706 stimulating, promoting or activating activity
• CPC Class Codes: G01N 2333/75 Fibrin; Fibrinogen
• CPC Class Codes: G01N 33/543 with an insoluble carrier for immobilising immunochemicals
• CPC Class Codes: G01N 33/6887 from muscle, cartilage or connective tissue
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 40/10 Signal processing, e.g. from mass spectrometry [MS] or from PCR

Abstract

A method of measuring an analyte amount in a whole blood sample, including:

• • measuring the haematocrit level of the whole blood sample;
  • measuring an analyte amount directly in the whole blood sample; and
  • calculating a corrected analyte amount according to relation:
    D_P=P_a(D_ST, D_H)
    where D_P is the corrected analyte amount, D_ST is the measured analyte amount, D_H is the measured haematocrit level, and P_a is a non-constant polynomial of a degree greater than or equal to 1 having as indeterminate values the measured analyte amount, D_ST, and the measured haematocrit level, D_H, and having its polynomial coefficients depending on the analyte.

Claims

1. A method of measuring an amount of analyte in a whole blood sample, wherein the method comprises:

performing a calibration of the method,

wherein the calibration comprises;

providing a plurality of calibration whole blood samples;

measuring an haematocrit level and an analyte amount directly in each of the plurality of calibration whole blood samples;

measuring an analyte amount in a plasma sample from each of the plurality of calibration whole blood samples; and

calculating polynomial coefficients of relation D_P=P_a(D_ST, D_H) from values of haematocrit level and analyte amount measured in the plurality of calibration whole blood samples, and values of analyte amount measured in the plasma samples from the plurality of calibration whole blood samples,

where D_P is the measured analyte amount in plasma, D_ST is the measured analyte amount in whole blood, D_H is the measured haematocrit level, and P_a is a non-constant polynomial of a degree greater than or equal to 1 having as indeterminate values the measured analyte amount, D_ST, and the measured haematocrit level, D_H, said relation having polynomial coefficients depending on the analyte;

measuring an analyte amount directly in the whole blood sample;

calculating a corrected analyte amount according to the relation;

D_P=P_a(D_ST, D_H)

where D_P is the corrected analyte amount, D_STis the measured analyte amount, and D_H is the measured haematocrit level P_a D_ST D_H; and

providing the calculated value of the corrected analyte amount.

2. The method of claim 1, wherein polynomial P_a comprises product D_ST×

D_H of the measured analyte amount D_ST by the measured haematocrit level D_H.

3. The method of claim 1, wherein the corrected analyte amount is calculated according to relation:

D_P=a₀+a₁×

D_ST+a₂×

D_H+a₁₂×

D_ST×

D_H

where a₀, a₁, a₂ and a₁₂ are predetermined coefficients depending on the analyte.

4. The method of claim 1, wherein the analyte amount/concentration is measured according to an immunoassay technique of ELISA type, of ELFA type, or of immunocapture type.

5. The method of claim 2, wherein the corrected analyte amount is calculated according to relation:

D_P=a₀+a₁×

D_ST+a₂×

D_H+a₁₂×

D_ST×

D_H

where a₀, a₁, a₂ and a₁₂ are predetermined coefficients depending on the analyte.

6. The method of claim 1, wherein the calibration includes performing a verification comprising:

providing a plurality of verification whole blood samples;

measuring an haematocrit level and an analyte amount directly in each of the plurality of verification whole blood samples;

measuring an analyte amount in a plasma sample from each of the plurality of verification whole blood samples;

calculating an analyte amount in the plasma sample from each of the plurality of verification whole blood samples according to the polynomial relation D_P=P_a(D_ST, D_H) from the values of haematocrit level and analyte amount measured in each of the plurality of verification whole blood samples; and

calculating a relative error between the calculated values and the measured values of the analyte amounts in the plasma samples from the plurality of verification whole blood samples.

7. The method of claim 6, comprising comparing the relative error to at least one threshold, wherein:

if the relative error does not exceed the at least one of the at least one threshold, the calibration is completed, and

if the relative error exceeds at least one of the at least one threshold, the verification comprises repeating the calculation of the calibration with a non-constant polynomial P_a having one order higher.

8. A method of measuring an analyte concentration in a whole blood sample, wherein the method wherein the method comprises:

performing a calibration of the method

wherein the calibration comprises;

providing a plurality of calibration whole blood samples;

measuring an haematocrit level and an analyte amount directly in each of the plurality of calibration whole blood samples and transforming the measured value of analyte amount in each of the plurality of calibration whole blood samples into a concentration;

measuring an analyte amount in a plasma sample from each of the plurality of calibration whole blood samples and transforming the measured value of analyte amount in each of the plurality of plasma samples into a concentration; and

calculating polynomial coefficients of relation C_P=P_a(C_ST, D_H) from values of haematocrit level and analyte concentration measured in the plurality of calibration whole blood samples, and values of analvte concentration measured in the plasma samples from the plurality of calibration whole blood samples,

where C_P is the measured analyte concentration in plasma, C_ST is the measured analyte concentration in whole blood, D_H is the measured haematocrit level, and P_a is a non-constant polynomial of a degree greater than or equal to 1 having as indeterminate values the measured analyte concentration, C_ST, and the measured haematocrit level D_H, said relation having polynomial coefficients depending on the analyte;

measuring an analyte amount directly in the whole blood sample and transforming the measured amount into a concentration by dividing the measured amount by the sample volume; and

calculating a corrected analyte concentration according to the relation;

C_P=P_a(C_ST, D_H)

where C_P is the corrected analyte concentration, C_ST is the measured analyte concentration, and D_H is the measured haematocrit level P_a C_ST D_H; and

providing the calculated value of the corrected analyte concentration.

9. The method of claim 8, wherein the corrected analyte concentration is calculated according to relation:

C_P=a′

₀+a₁×

C_ST+a′

₂×

D_H+a₁₂×

C_ST×

D_H

where a′

₀, a₁, a′

₂ and a₁₂ are predetermined coefficients depending on the analyte.

10. The method of claim 9, wherein the analyte is a D-dimer, and wherein:

a′

₀ is in the range from −

29.311×

0.9 to −

29.311×

1.1;

a₁ is in the range from 0.788×

0.9 to 0.788×

1.1;

a′

₂ is in the range from 0.702×

0.9 to 0.702×

1.1; and

a₁₂ is in the range from 0.018×

0.9 to 0.018×

1.1.

11. The method according to claim 9, wherein:

a′

₀=−

29.311;

a₁=0.788;

a′

₂=0.702; and

a₁₂=0.018.

12. The method of claim 9, wherein the analyte is a cardiac troponin I, and wherein:

a′

₀ is in the range from −

0.0052×

0.9 to −

0.0052×

1.1;

a₁ is in the range from 0.9155×

0.9 to 0.9155×

1.1;

a′

₂ is in the range from 0.0002×

0.9 to 0.0002×

1.1; and

a₁₂ is in the range from 0.0072×

0.9 to 0.0072×

1.1.

13. The method according to claim 12, wherein:

a′

₀=−

0.0052;

a₁ =0.9155;

a′

₂=0.0002; and

a₁₂=0.0072.

14. The method of claim 8, wherein polynomial P_a comprises product C_ST×

D_H of the measured analyte concentration C_ST by the measured haematocrit level D_H.

15. The method of claim 14, wherein the corrected analyte concentration is calculated according to relation:

C_P=a′

₀+a₁×

C_ST+a′

₂×

D_H+a₁₂×

C_ST×

D_H

where a′

₀, a₁,a′

₂ and a₁₂ are predetermined coefficients depending on the analyte.

16. The method of claim 15, wherein the analyte is a D-dimer, and wherein:

a′

₀ is in the range from −

29.311×

0.9 to −

29.311×

1.1;

a₁ is in the range from 0.788×

0.9 to 0.788×

1.1;

a′

₂ is in the range from 0.702×

0.9 to 0.702×

1.1; and

a₁₂ is in the range from 0.018×

0.9 to 0.018×

1.1.

17. The method according to claim 15, wherein:

a′

₀=−

29.311;

a₁=0.788;

a′

₂=0.702; and

a₁₂=0.018.

18. The method of claim 15, wherein the analyte is a cardiac troponin I, and wherein:

a′

₀ is in the range from −

0.0052×

0.9 to −

0.0052×

1.1;

a₁ is in the range from 0.9155×

0.9 to 0.9155×

1.1;

a′

₂ is in the range from 0.0002×

0.9 to 0.0002×

1.1; and

a₁₂ is in the range from 0.0072×

0.9 to 0.0072×

1.1.

19. The method of claim 8, wherein the calibration includes performing a verification comprising:

providing a plurality of verification whole blood samples;

measuring an haematocrit level and an analyte amount directly in each of the plurality of verification whole blood samples and transforming the measured value of analyte amount in each of the plurality of verification whole blood samples into a concentration;

measuring an analyte amount in a plasma sample from each of the plurality of verification whole blood samples and transforming the measured value of analyte amount in each of the plurality of plasma samples from the plurality of verification whole blood samples into a concentration;

calculating an analyte amount in the plasma sample from each of the plurality of verification whole blood samples according to the polynomial relation C_P=P_a(C_ST, D_H) from the values of haematocrit level and analyte concentration measured in each of the plurality of verification whole blood samples; and

calculating a relative error between the calculated values and the measured values of the analyte concentration in the plasma samples from the plurality of verification whole blood samples.

20. The method of claim 19, comprising comparing the relative error to at least one threshold, wherein:

if the relative error does not exceed the at least one of the at least one threshold, the calibration is completed, and

if the relative error exceeds at least one of the at least one threshold, the verification comprises repeating the calculation of the calibration with a non-constant polynomial P_a having one order higher.

21. A device for measuring the plasmatic amount of an analyte in a whole blood sample, wherein the device comprises:

means for performing a calibration of the device,

wherein the calibration comprises;

providing a plurality of calibration whole blood samples;

measuring an haematocrit level and an analyte amount directly in each of the plurality of calibration whole blood samples;

measuring an analyte amount in a plasma sample from each of the plurality of calibration whole blood samples; and

calculating polynomial coefficients of relation D_P=P_a(D_ST, D_H) from values of haematocrit level and analyte amount measured in the plurality of calibration whole blood samples, and values of analyte amount measured in the plasma samples from the plurality of calibration whole blood samples,

where D_P is the measured analyte amount in plasma, D_ST is the measured analyte amount in whole blood, D_H is the measured haematocrit level, and P_a is a non-constant polynomial of a degree greater than or equal to 1 having as indeterminate values the measured analyte amount, D_ST, and the measured haematocrit level, D_H, said relation having polynomial coefficients depending on the analvte;

means for receiving said whole blood sample;

means for measuring the total analyte amount in the whole blood sample;

means for calculating a corrected analyte amount according to the relation;

D _P=P_a(D_ST, D_H)

where D_P is the corrected analyte amount, D_ST is the measured analyte amount, and D_H is the measured haematocrit level P_a D_ST D_H .

22. The device of claim 21, which is capable of implementing a method of measuring an amount of analyte in a whole blood sample, wherein the method comprises:

measuring the haematocrit level of the whole blood sample;

measuring an analyte amount directly in the whole blood sample; and

calculating a corrected analyte amount according to relation;

D_P=P_a(D_ST, D_H)

where D_P is the corrected analyte amount, D_ST is the measured analyte amount, D_H is the measured haematocrit level, and P_a is a non-constant polynomial of a degree greater than or equal to 1 having as indeterminate values the measured analyte amount, D_ST, and the measured haematocrit level, D_H, and having its polynomial coefficients depending on the analyte,

wherein polynomial P_a comprises product D_ST×

D_H of the measured analyte amount D_ST by the measured haematocrit level D_H.

23. A device for measuring the plasmatic analyte concentration in a whole blood sample, wherein the device comprises:

means for performing a calibration of the device,

wherein the calibration comprises;

providing a plurality of calibration whole blood samples;

measuring an haematocrit level and an analyte amount directly in each of the plurality of calibration whole blood samples and transforming the measured value of analyte amount in each of the plurality calibration whole blood samples into a concentration;

measuring an analyte amount in a plasma sample from each of the plurality of calibration whole blood samples and transforming the measured value of analyte amount in each of the plurality of plasma samples into a concentration; and

calculating polynomial coefficients of relation C_P=P_a(C_ST, D_H) from values of haematocrit level and analyte concentration measured in the plurality of calibration whole blood samples, and values of analyte concentration measured in the plasma samples from the plurality of calibration whole blood samples,

where C_P is the measured analyte concentration in plasma, C_ST is the measured analyte concentration in whole blood, D_H is the measured haematocrit level, and P_a is a non-constant polynomial of a degree greater than or equal to 1 having as indeterminate values the measured analyte concentration, C_ST, and the measured haematocrit level, D_H, said relation having polynomial coefficients depending on the analyte;

means for receiving said whole blood sample;

means for measuring the total analyte amount in the whole blood sample;

means for transforming the analyte amount into a concentration;

means for inputting or for measuring the haematocrit level in the whole blood sample;

means for calculating a corrected analyte concentration according to the relation;

C_P=P_a(C_ST, D_H)

where C_P is the corrected analyte concentration, C_ST is the analyte concentration calculated from the measured amount and from the sample volume, and D_H is the measured haematocrit level, P_a C_ST D_H.

24. The device of claim 23, which is capable of implementing a method of measuring an analyte concentration in a whole blood sample, wherein the method comprises:

measuring the haematocrit level of the whole blood sample;

measuring an analyte amount directly in the whole blood sample and transforming the measured amount into a concentration by dividing the measured amount by the sample volume; and

calculating a corrected analyte concentration according to relation;

C_P=P_a(C_ST, D_H)

where C_P is the corrected analyte concentration, C_ST is the measured analyte concentration, D_H is the measured haematocrit level, and P_a is a non-constant polynomial of a degree greater than or equal to 1 having as indeterminate values the measured analyte concentration, C_ST, and the measured haematocrit level, D_H, and having its polynomial coefficients depending on the analyte,

wherein polynomial P_a comprises product C_ST×

D_H of the measured analyte concentration C_ST by the measured haematocrit level D_H.