Characterizing an Optimal Predictive Modeling Framework for Prediction of Adverse Drug Events Jon Duke, MD MS, Xiaochun Li PhD, Zuoyi Zhang PhD EDM Forum June 7 th 2014

Project Goal/Background The ability to identify patients at increased risk of an adverse drug event at the time of prescribing may improve patient safety The optimal methods for performing such predictive modeling using routinely collected clinical data are unknown The goal of this study is to assess the feasibility and optimal methods for predicting risk of ADEs of differing prevalence levels using observational data

Drug Safety Alert Override Rate 49% - 96%

Methods We selected three drug-outcome pairs of varying frequency ACE-I and Hyperkalemia (Frequent) SSRIs/SNRIs and Hyponatremia (Infrequent) Statins and Rhabdomyolysis (Rare) We defined each outcome phenotype based on diagnoses (ICD-9) and labs (LOINC)

Methods Applied a new user design for cohort selection – Drug exposure initiation must be ≥ 1 year after entering the observation period Source dataset: 2.2 million patients in OMOP CDM format – Drugs, diagnoses, labs, procedures, demographics Applied three modeling methods to each drug- outcome pair – Multiple regression – Classification and regression trees (CART) – Random forest

Performance Evaluation and Comparators Used an 2:1 random training-test split Modeled for event at 30, 90, and 365 days In addition to measuring performance using the target drug-outcome pairs, also applied the derived models to predicting risk of the outcome in similar cohorts without exposure – Comparator Cohorts Hyperkalemia – Amlodipine Hyponatremia – Bupropion Rhabdomyolysis – Niacin

Results (no surprise) Random Forest performs best – Mean AUC for all outcomes – RF > LR > CART - 80% > 76% > 71% More common outcomes perform better AUC 0.86 AUC 0.7

Results (surprise) Models performed equally as well on the comparator groups in terms of predicting the likelihood of a given outcome – Hyperkalemia with Amlodipine AUC 84% – Hyponatremia with Bupropion AUC 82% – Rhabdomyolysis with Niacin AUC 76%

Results Despite reasonable AUCs, PPVs remain mediocre for best performing models – Hyperkalemia with ACE 35% – Hyponatremia with SSRI 28% – Rhabdomyolysis with Statin 2% Skewing towards better specificity (setting threshold to catch only highest risk 10%) – Slight improvements to 38%, 37%, 4%

Discussion Putting our findings in the context of developing real-world CDS systems based on individual risk – Random forest best, but logistic regression pretty close and may be more appealing for displaying RFs – Developing individual models for each drug-outcome pair may prove unnecessary. One model for each outcome may be sufficient – Even with risk-based alerting, poor specificity / alert fatigue will remain a problem for rare adverse events

Conclusions Personalized risk calculation may be beneficial in CDS, but effectiveness will be highly dependent on implementation strategy (e.g., highlighting vs. suppressing alerts) Study limitations include application setting, unknown misclassification existence, possibly incomplete lists of covariates Further research required regarding using common models for individual outcomes

Thank You