Imperfect Gold Standards for Biomarker Evaluation. Rebecca A. Betensky Conference on Statistical Issues in Clinical Trials University of Pennsylvania April 18, 2012. Outline. Motivation: need for kidney injury biomarkers for diagnosis of acute kidney injury (AKI)
Rebecca A. Betensky
Conference on Statistical Issues in Clinical Trials
University of Pennsylvania
April 18, 2012
Idealized example of perfect novel biomarker
imperfect gold standard sensitivity=80%, specificity=80%
Relative to imperfect gold standard, a perfect novel biomarker will have apparent sensitivity of 50% and apparent specificity of 64/68=94%.
At lower prevalence, dominant effect of imperfect gold standard is on perfect biomarker’s apparent sensitivity:
apparent sens= apparent spec=
At prevalence of 20%, apparent sensitivity of perfect biomarker is 100% and apparent specificity is 84%. The bounds of the apparent AUC are 0.84-1.00.
Even rare false positives (imperfect gold standard spec=99%) lead to apparent sensitivity of 86% and bounds of apparent AUC of 0.72-0.98.
What can we learn for dialysis”.imperfect novel biomarker?
does not imply independence given disease:
Conditional independence may not be possible at a given disease prevalence.
Under conditional independence, split into two tables, with some constraints:
p=P(D=1)= a+ b+c+ d
Ignoring sampling variability, for p(0.285,0.715), conditional independence is not possible.
Waikar SS, Betensky RA, Emerson SC, Bonventre JV (2012). Imperfect gold standards for kidney injury biomarker evaluation. J Am Soc Nephrol 23: 13-21.
Emerson SC, Waikar SS, Bonventre JV, Betensky RA (2012). Biomarker validation with an imperfect reference: issues and bounds. Unpublished manuscript.
With low prevalence, maintaining high specificity is more important than high sensitivity.