We studied how lagged linear regression can be used to detect the physiologic effects of drugs from data in the electronic health record (EHR). We systematically examined the effect of methodological variations ((i) time series construction, (ii) temporal parameterization, (iii) intra-subject normalization, (iv) differencing (lagged rates of change achieved by taking differences between consecutive measurements), (v) explanatory variables, and (vi) regression models) on performance of lagged linear methods in this context. We generated two gold standards (one knowledge-base derived, one expert-curated) for expected pairwise relationships between 7 drugs and 4 labs, and evaluated how the 64 unique combinations of methodological perturbations reproduce gold standards. Our 28 cohorts included patients in Columbia University Medical Center/NewYork-Presbyterian Hospital clinical database. The most accurate methods achieved AUROC of 0.794 for knowledge-base derived gold standard (95%CI [0.741, 0.847]) and 0.705 for expert-curated gold standard (95% CI [0.629, 0.781]). We observed a 0.633 mean AUROC (95%CI [0.610, 0.657], expert-curated gold standard) across all methods that re-parameterize time according to sequence and use either a joint autoregressive model with differencing or an independent lag model without differencing. The complement of this set of methods achieved a mean AUROC close to 0.5, indicating the importance of these choices. We conclude that time- series analysis of EHR data will likely rely on some of the beneficial pre-processing and modeling methodologies identified, and will certainly benefit from continued careful analysis of methodological perturbations. This study found that methodological variations, such as pre-processing and representations, significantly affect results, exposing the importance of evaluating these components when comparing machine-learning methods.
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