save yourself Marylyn D Ritchie June 29, 2015 Regression analysis - PowerPoint PPT Presentation

DANGER: Understand your data, save yourself Marylyn D Ritchie June 29, 2015

Regression analysis issue • In pediatric null variant PheWAS, issues with replication emerged 1) Some phenotypes were present in only discovery or replication, but not both 2) Some regression models were not coverging • Simultaneously, AAA quick PheWAS for top hits from GWAS noted convergence issue • Our investigations began….

Convergence is an issue • Evaluated previous GWAS analyses and the majority of them had convergence issues • What does this mean: – Each variable in the model will have a p-value associated with it, and in some software, the regression model will also have a p-value associated with it, but the p-values may not be valid • Bigger problem is that you need to look carefully – Some software does not tell you the model did not converge

Comparison between PLATO, PLINK, R, Minitab, SAS Model : rs328 and 272.1 PLATO Output: Outcome Var1_ID Var1_Pos Var1_MAF Num_Missing Num_Cases Converged Var1_Pval Var1_beta Var1_SE LRT_Pvalue 272.1 rs328 8:19819724 G:0.0972 772 394 0 2.23585e-05 -0.663193 0.156416 1 PLINK Output: Same in PLINK1.07 and PLINK1.9 CHR SNP BP A1 TEST NMISS OR STAT P 8 rs328 19819724 G ADD 19728 NA NA NA Note: No warning from PLINK R output:

Comparison between PLATO, PLINK, R, Minitab, SAS Model : rs328 and 272.1 SAS: It provides the following warning message: Warning: The maximum likelihood estimate may not exist. Warning: The LOGISTIC procedure continues in spite of the above warning. Results shown are based on the last maximum likelihood iteration. Validity of the model fit is questionable. Minitab:

Comparison between PLINK1.07 and PLINK1.9 PLATO OUTPUT: Var1_ID Var1_Pos Var1_MAF Num_Missing Num_Cases Converged Var1_Pval Var1_beta Var1_SE LRT_Pval rs11774033 8:137585559 T:0.981774 1 308 0 0.0469422 -0.570091 0.286 1 PLINK 1.07: CHR SNP BP A1 TEST NMISS OR STAT P 8 rs11774033 137585559 C ADD 14457 NA NA NA PLINK 1.9: CHR SNP BP A1 TEST NMISS OR STAT P 8 rs11774033 137585559 C ADD 14457 1.799 2.046 0.04079

Why is this happening? AAA - did not converge

Why is this happening? Resistant Hypertension - did not converge

Why is this happening? • Due to the nature of the imputation and the potential for stratification, we need to adjust models for site, platform, sex, and PCs • Having only cases or controls in some of these strata leads to non-convergence • If you evaluate the clinical model alone, without SNP data, you will identify this early • Such investigations are not typically done in PheWAS

Corrections • Two options to deal with this issue 1) Drop any rows from the table where you have zeros • Caveat: may become small sample size • Caveat: works best when your case or control group with data present is large – no convergence issue when # cases = 10 – yes convergence issue when # controls = 100 2) Use firth regression • Caveat: not available in PLINK • Caveat: may run slower in R than standard regression; (however, not slower in PLATO)

Hypothyroidism- Converged

Firth regression comparison between PLATO and SAS PLATO Output SAS Output ICD-9 code: 272.1 SNP: rs328 CHR:BP: 8:19819724 Allele:MAF: G:0.0972208 Num_Missing: 772 Cases: 394 Converged: 1 Raw_LRT_Pval: 2.5945569177565631e-06 SNP_Pval: 2.22132e-05 SNP_Beta: -0.651743 SNP_SE: 0.153662 LRT_Pval: 2.59456e-06

Conclusion • Be cautious when combining data from multiple sites where case and control contributions are biased • Look carefully at regression results to confirm convergence

Thank you for finding, evaluating, solving this issue….. Yuki Bradford Molly Hall Sarah Pendergrass Anurag Verma Shefali Verma John Wallace