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Diagnostic Products Corporation Beyond Reference Intervals: Interpretive Frameworks for Immunoassay A. Paul Durham Dir. Scientific Publications
Modern Reference Range Analysis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],IFCC: International Federation of Clinical Chemistry and Laboratory Medicine
The IFCC Approach in Perspective ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],EBM: evidence-based medicine
Evidence-based Clinical Biochemistry ,[object Object],[object Object],[object Object],[object Object],As reported in: Moore RA. Ann Clin Biochem 1997;34:3. David L. Sackett removal of the unhelpful concept of  normality  or  abnormality
Strictures on Normality, 1 ,[object Object],[object Object],[object Object],[object Object],Sackett, in: Knottnerus, ed. Evidence Base of Clinical Diagnosis (BMJ) 2002:19.
 
Changing Attitudes — Ancient History ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Hoffmann, JAMA 1963;185:864.  Henny et al, CCLM 2000;38:595.
Strictures on Normality, 2 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Sackett, in: Knottnerus, ed. Evidence Base of Clinical Diagnosis (BMJ) 2002:19.
[object Object],[object Object],[object Object],[object Object],[object Object],IFCC Tradition, 1 Burtis & Ashwood, edd. Tietz Textbook of Clinical Chemistry, 3rd Ed. 1999:336. Helge Erik Solberg
Extending the IFCC Technical Repertoire ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
IFCC Tradition, 2 ,[object Object],[object Object],[object Object],[object Object],Eugene K. Harris
Rio2003 Data from: Semjonow.
Data from: Semjonow. Rio2003 Mean  and  variance increase with age.
Reference Values (IFCC) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Reference Intervals (IFCC) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],“ 37ºC”
[object Object],[object Object],The Roots of Minimalism * Soldin et al. Pediatric Reference Ranges, 4th Ed. AACC Press, 2003:xvii. “ ... for the most part, when a physician ... seeks information about reference ranges, that is all he or she is interested in ! ” *
The “AACC” Perspective ,[object Object],[object Object],[object Object],[object Object],[object Object],Steven J. Soldin Jocelyn Hicks
Insulin-like Growth Factor I (IGF-I) Soldin et al. Pediatric Reference Ranges, 4th Ed. AACC Press, 2003:125. Rio2003
AACC’s PRR4 — Typical Annotations Soldin et al. Pediatric Reference Ranges, 4th Ed. AACC Press, 2003:178, from T4 section. Hospitalized patients Hoffmann-like technique Regression transfer
Cortisol in Pregnancy, and Post Partum Gillian Lockitch Handbook of Diagnostic Biochemistry and Hematology in Normal Pregnancy. CRC Press, 1993.
[object Object],[object Object],[object Object],[object Object],The Roots of Minimalism
The Laboratory-Physician Interface ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
What Gets Lost? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Representative Entries ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Assimilation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Strictures on Normality, 3 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Sackett, in: Knottnerus, ed. Evidence Base of Clinical Diagnosis (BMJ) 2002:19.
A Transparent Fallacy ,[object Object],[object Object],[object Object],These are the [central 95%] limits [estimated] for serum ferritin results from normal adults. Adults are normal only if they have ferritin results within these limits.
Resisting Assimilation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Box and Whisker Box and Fishbone Rio2003 central 50%, 80%, 90%, 95% implementation- dependent “ outliers”
Busselton Study, 2002. Rio2003 Men: Calculated Free Testosterone (cFT)
Tromso Study Rio2003 Svartberg et al. JCEM 2003;88:3099. Publication’s use of means and parametric statistics directly, on data sets likely to be nongaussian,  makes it unreliable to estimate month-related reference ranges by meta-analysis.
Elmlinger, 2002. IGF-I / IGFBP-3 Ratio, by Tanner Stage Rio2003
Bivariate Box-and-Fishbone Plots Log SHBG, on Body Mass Index Maastricht / Diepenbeek Postmenopausal Study, 2002. Central 95% Light Blue Patch Central 50% Blue Patch Central 80% Dark Blue Line
Information Sharing ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Information Sharing ,[object Object],[object Object],[object Object],[object Object],[object Object]
A Word of Caution… ,[object Object],[object Object],[object Object],[object Object],[object Object]
EBM and IFCC: Points of Agreement ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
IFCC: Establishing and Using RVs ,[object Object],[object Object],[object Object],[object Object],[object Object],Interpretation:   Translate test result for a patient of that description to a  (per)centile,  or multivariate distance measure. RVs: reference values.
“ Interpretation by Comparison” * ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],* Solberg, in: Tietz3 1999:336.  M.: Mahalanobis, or multivariate.
“ Interpretation by Comparison” * ,[object Object],[object Object],[object Object],[object Object],[object Object],* Solberg, in: Tietz3 1999:336.
Taking a Step Beyond … ,[object Object],[object Object],[object Object],[object Object]
The Zen of Normal Ranges ,[object Object],[object Object],[object Object],[object Object],Interpretation:   Translate patient result to probability / likelihood of some disease .
For the Unenlightened ... ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Interpretation:   Translate patient result to  likelihood ratio (LR).
Interpretation via Two Distributions Data from: Stephan et al. Clin Chem 2002;48:1279. Density BPH, N=292 PCa, N=567 Likelihood Ratio Rio2003
Disease-oriented Practicalities ,[object Object],[object Object],[object Object],[object Object],[object Object]
“ Reference Distributions, not Intervals” ,[object Object],[object Object],[object Object],Gordon Guyatt Presentation at AACC National Meeting, 30 July 2002.
Lab Tests: Two Uses (Guyatt) ,[object Object],[object Object],[object Object],[object Object],Notes on Guyatt’s AACC presentation, 30 July 2002.
Growth Chart “ The use of DS specific growth charts is important for diagnosis of associated diseases, such as coeliac disease and hypothyroidism, which may further impair growth.” Myrelid et al. Arch Dis Child 2002;87:97. Rio2003 Height, Boys Down Syndrome Children
National Height Velocity Standards Hermanussen et al. Horm Res 2002;58:71. Differences partly due to data analysis!
Elmlinger, 2002. Rio2003 IGF-I, in Children
Conclusions ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],ANNs: artificial neural networks.
sIgE Rio2003 Allergen-specific IgE assays: Concentrations translatable into “Class” scores. Decision Level   0.35 kU/L Detection Limits:   A: 0.35 kU/L   B: 0.10 kU/L No finite upper limit (dilutions).
‘ Cumulative Distribution Analysis’ Plots “ CDA” plots: Krouwer. Clin Chem 1987;33:2305. sIgE assays compared to skin prick testing
“ Censored” ROC Plot ROC plot: receiver operating characteristic plot. Curves don’t extend to the corner.
Diagnostic Products Corporation www.DPCweb.com    technical documents [email_address] D922b Rio2003
Changing Attitudes — Modern Debate ,[object Object],[object Object],[object Object],[object Object],[object Object]
Reference Intervals (IFCC) ,[object Object],[object Object],[object Object],[object Object]
The “Reference Population” (IFCC) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
The “Underlying Distribution” ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Highest result from N=3 sample expected to fall at about 80th centile (Z=+0.85 SD),  on average . Highest and lowest values expected to enclose central 95%, on average , only for N    28 & higher. Centile Z-score (SDI)

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Bri D926

  • 1. Diagnostic Products Corporation Beyond Reference Intervals: Interpretive Frameworks for Immunoassay A. Paul Durham Dir. Scientific Publications
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  • 12. Rio2003 Data from: Semjonow.
  • 13. Data from: Semjonow. Rio2003 Mean and variance increase with age.
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  • 18. Insulin-like Growth Factor I (IGF-I) Soldin et al. Pediatric Reference Ranges, 4th Ed. AACC Press, 2003:125. Rio2003
  • 19. AACC’s PRR4 — Typical Annotations Soldin et al. Pediatric Reference Ranges, 4th Ed. AACC Press, 2003:178, from T4 section. Hospitalized patients Hoffmann-like technique Regression transfer
  • 20. Cortisol in Pregnancy, and Post Partum Gillian Lockitch Handbook of Diagnostic Biochemistry and Hematology in Normal Pregnancy. CRC Press, 1993.
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  • 29. Box and Whisker Box and Fishbone Rio2003 central 50%, 80%, 90%, 95% implementation- dependent “ outliers”
  • 30. Busselton Study, 2002. Rio2003 Men: Calculated Free Testosterone (cFT)
  • 31. Tromso Study Rio2003 Svartberg et al. JCEM 2003;88:3099. Publication’s use of means and parametric statistics directly, on data sets likely to be nongaussian, makes it unreliable to estimate month-related reference ranges by meta-analysis.
  • 32. Elmlinger, 2002. IGF-I / IGFBP-3 Ratio, by Tanner Stage Rio2003
  • 33. Bivariate Box-and-Fishbone Plots Log SHBG, on Body Mass Index Maastricht / Diepenbeek Postmenopausal Study, 2002. Central 95% Light Blue Patch Central 50% Blue Patch Central 80% Dark Blue Line
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  • 44. Interpretation via Two Distributions Data from: Stephan et al. Clin Chem 2002;48:1279. Density BPH, N=292 PCa, N=567 Likelihood Ratio Rio2003
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  • 48. Growth Chart “ The use of DS specific growth charts is important for diagnosis of associated diseases, such as coeliac disease and hypothyroidism, which may further impair growth.” Myrelid et al. Arch Dis Child 2002;87:97. Rio2003 Height, Boys Down Syndrome Children
  • 49. National Height Velocity Standards Hermanussen et al. Horm Res 2002;58:71. Differences partly due to data analysis!
  • 50. Elmlinger, 2002. Rio2003 IGF-I, in Children
  • 51.
  • 52. sIgE Rio2003 Allergen-specific IgE assays: Concentrations translatable into “Class” scores. Decision Level 0.35 kU/L Detection Limits: A: 0.35 kU/L B: 0.10 kU/L No finite upper limit (dilutions).
  • 53. ‘ Cumulative Distribution Analysis’ Plots “ CDA” plots: Krouwer. Clin Chem 1987;33:2305. sIgE assays compared to skin prick testing
  • 54. “ Censored” ROC Plot ROC plot: receiver operating characteristic plot. Curves don’t extend to the corner.
  • 55. Diagnostic Products Corporation www.DPCweb.com  technical documents [email_address] D922b Rio2003
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  • 60. Highest result from N=3 sample expected to fall at about 80th centile (Z=+0.85 SD), on average . Highest and lowest values expected to enclose central 95%, on average , only for N  28 & higher. Centile Z-score (SDI)