# Presentation: 062465

## EDRN Approaches to Biomarker Validation

**DMCC Statisticians**
**Fred Hutchinson Cancer Research Center**
- Margaret Pepe
-  Ziding Feng, Mark Thornquist, Yingye Zheng, and Ross Prentice

## Biomarker for What Purpose? 

-  Early Detection Screening
-  Diagnosis
-  Prognosis
-  Risk Prediction
- Treatment Selection
- Surrogate Outcome
- Exposure

## Biomarker with What Performance? 

- Measure of performance is context-dependent
- Acceptable levels of performance also context-dependent

## Breast Cancer Collaborative Group Study 

- Context = diagnostic biopsy for suspicious lesion
- Biomarker purpose = diagnostic
- Decision rule = “biopsy only if biomarker positive”
- Performance measure = reduction in unnecessary biopsies
- 		                   reduction in cancers detected
- Acceptable levels of performance: True Positive Rate _>_ 98%
- 			                       False Positive Rate _<_ 75%
- No formal decision analysis to set these criteria

## Another Purpose	

- Reduce unnecessary mammograms by applying biomarker ***before*** mammogram
- FPF _<_ 75% would have enormous impact

## Ovarian Cancer Screening of Healthy Population

- Performance  =  disease detected early                     			         false referral for work-up
- FPF _<_ 2%
- TPF for late stage cancer at 1 year before clinical diagnosis > 20%

## Risk Prediction 

- Model individual’s risk of bad outcome given his marker value(s)
-    Well calibrated model?
-     Performance = Useful delineation of risk distribution     	across the population?

## Risk Model of Biopsy Proven High Grade Prostate Cancer in the PCPT Study Placebo Arm (n=5519) 

**Factor****	****Log Odds Ratio****	****P-value**
- Constant	   -5.94	--
- Log (PSA)	   1.30	<0.001
- Age (years)	    0.03	0.020
- DRE	0.99	<0.001
- Prior biopsy	   -1.37	0.040

## Risk Model of Biopsy Proven High Grade Prostate Cancer in the PCPT Study Placebo Arm (n=5519) 

## Phases of Biomarker Development for Early Detection 

- Phase 1	  Discovery
- Phase 2	  Diagnostic Validation
- Phase 3	  Early Detection Validation*
- Phase 4	  Prospective Application
- Phase 5	  Randomized Trial with Treatment
- EDRN focus on phase 2 and 3 studies
- Phases 4 and 5 involve actions based on biomarker result.  Consequences to patients should be evaluated.

## Key Design Issues in Definitive Validation 

- Study population is that for intended clinical application.  Sufficiently general? Multiple institutions?
- Marker well defined in advance
- Validation separate from discovery
- Combination pre-defined
- Threshold need not be predefined?
- Assay as intended for clinical use?
- Minimally acceptable performance criteria to be met. Justification?Anticipated/desirable performance drives sample size calculations

## Key Design Issues in Definitive Validation 

- Cases-controls from the same population typically require prospective collection of samples for storage.Existing repositories (e.g., PLCO, WHI) or create our own
- Blinding: collection, storage and assay
- Random selection of eligible cases from repository. Stratify on disease characteristics and other factors?
- Random selection of controls
- Several control groups possible
- Matched to cases if appropriate (potential pitfalls here)
- Early termination rules. Adjustments in analysis?

## Standards for Design of the Definitive* Study

- Therapeutics:  the randomized placebo controlled clinical trial
- Biomarkers:  the prospective collection blinded evaluation study

## Questions Addressed in Analysis 

- Is performance good enough for the clinical application?                                                              e.g., in the breast cancer diagnostic study:  using the threshold corresponding to TPR=98% is the upper confidence limit for FPR _<_ 75%?
- What factors substantially affect biomarker values in controls? Is covariate adjustment necessary?
- 	e.g., stratify for study site?
- 	e.g., adjust for age?

## Study site (Z) affects biomarker distributions but not discrimination.  Equal prevalence across study sites.

## Study site (Z) affects biomarker distributions but not discrimination.  Confounding caused by differing prevalence across study sites 

## Physician’s Health Study, PSA as a marker for Prostate Cancer Matched on Age

- ROC(0.05) = 0.23	*A*ROC (0.05) = 0.36
- log(*PSA*) = 0 + 1 age + 

## Questions Addressed in Analysis 

- 3. What factors affect biomarker performance?
- 	Disease specific factors :  histology, stage ...
- 	Non-disease specific factors:  age, study site ...

- Performance varies with *X*

## Questions Addressed in Analysis

- 4. Incremental value of a marker over existing predictors
-    Comparative study
-    ROC curves for 	(i) baseline predictors
- 						(ii) marker and baseline
- Statistically significant effect in logistic regression is not enough
- Matching on baseline variables (e.g., age) can render incremental value non-identifiable.

## Example

*X*1 = log CA19-9	     X2 = log CA-125
- Logit*P*(*D*=1|*X*1,*X*2) = ** + **1*X*1* + ***2*X*2
* **exp(****2)* * = 1.54 **	**     (p*=0.002)

## Summary 

- Biomarker evaluation must be done in the context of clinical application and population of interest.
- Setting performance criteria is crucial and difficult
- Standards of practice are needed for definitive validation studies
- Design standards
- Reporting standards