# Presentation: 756669

## Critique of May 10, 2000 Report on theYale Hemorrhagic Stroke Project (HSP)

**Brian L. Strom, M.D., M.P.H.**
**Chair and Professor, Department of Biostatistics and Epidemiology**
**Director, Center for Clinical Epidemiology and Biostatistics**
**Professor of Biostatistics and Epidemiology, Professor of Medicine**
**Professor of Pharmacology**
**University of Pennsylvania School of Medicine**
**Consultant, Whitehall-Robins Healthcare**

## Critique of May 10, 2000 Report on theYale Hemorrhagic Stroke Project (HSP)

**Initiated due to spontaneous reports**
**Appropriate, because of severe limitations of spontaneous reports in evaluating cause**
**Huge, ambitious study**
**Thoughtfully designed**
**Methodologically problematic**
**Chance**
**Confounding**
**Bias**

## Chance

**Marginal power: designed to detect OR=5.0 with a 1-tailed test**
**Very small numbers of exposed cases = fragile results**
**3 (or 5) co-equal aims ******** alpha should be 0.0166 (0.01)**
**Inconsistent results in subgroups by gender and indication, suggest chance as an explanation**
**“****Dose-response relationship” never tested statistically**

## Key Results-All PPA

**Not exposed**

**Exposed**

**CVA**

**No CVA**

**664**

**27**

**1310**

**33**

**Adj OR = 1.49 (p>0.05)**

## Key Results-By Indication

**Not exposed**

**Exposed**

**CVA**

**No CVA**

**CVA**

**No CVA**

_**Cough/Cold**_

**Appetite**
_**Suppressants**_

**664**

**664**

**Adj OR = 1.23 (p>0.05)**

**Adj OR = 15.92 (p=0.013)**

**22**

**1310**

**32**

**1310**

**6**

**1**

## Key Results-Among Women

**Not exposed**

**Exposed**

**CVA**

**No CVA**

**CVA**

**No CVA**

_**All PPA: First Use**_

**Appetite**
_**Suppressants**_

**355**

**355**

**Adj OR = 3.13 (p=0.042)**

**Adj OR = 16.58 (p=0.011)**

**7**

**713**

**713**

**4**

**6**

**1**

## Confounding

**Controlled using conditional logistic regression, but sample size too small for valid modeling**
**Better approach would have used stratification and/or exclusion**

## Misclassification Bias

**?valid to combine subarachnoid hemorrhage and primary intracerebral hemorrhage?**

## Information Bias

**Valid drug histories always difficult to collect retrospectively**
**Valid drug histories would be much harder to collect from stroke patients, resulting in unequal recall**
** ****Great effort taken to collect good data, but validation procedure assures specificity, not sensitivity, and very few missed exposures in controls would eliminate association**

## Selection Bias

**Properly done case-control studies should be population-based**
**Cases**** **
**not representative of the entire population, unlike controls: ?increased exposures**
**?completeness of identified**
**Only 41% of those identified, were enrolled**
**Controls: **
**no info given on process and success of RDD**

## Conclusions

**Ambitious and well described**
**Major risk of information bias and selection bias**
**Underpowered ******** fragile, subject to change in results with even small errors**
**At best, this study suggests the possibility of an association between use of this common drug and this very uncommon outcome.  It does not prove it. **
**This association remains uncertain.**