Rishi J. Desai

Bowen Gu, Rishi J. Desai, Kueiyu Joshua Lin et al. · harvard

Large Language Models (LLMs) have shown promise in clinical applications through prompt engineering, allowing flexible clinical predictions. However, they struggle to produce reliable prediction probabilities, which are crucial for transparency and decision-making. While explicit prompts can lead LLMs to generate probability estimates, their numerical reasoning limitations raise concerns about reliability. We compared explicit probabilities from text generation to implicit probabilities derived from the likelihood of predicting the correct label token. Across six advanced open-source LLMs and five medical datasets, explicit probabilities consistently underperformed implicit probabilities in discrimination, precision, and recall. This discrepancy is more pronounced with smaller LLMs and imbalanced datasets, highlighting the need for cautious interpretation, improved probability estimation methods, and further research for clinical use of LLMs.

Gerard T. Portela, Jason B. Gibbons, Sebastian Schneeweiss et al.

Observational studies developing causal machine learning (ML) models for the prediction of individualized treatment effects (ITEs) seldom conduct empirical evaluations to assess the conditional exchangeability assumption. We aimed to evaluate the performance of these models under conditional exchangeability violations and the utility of negative control outcomes (NCOs) as a diagnostic. We conducted a simulation study to examine confounding bias in ITE estimates generated by causal forest and X-learner models under varying conditions, including the presence or absence of true heterogeneity. We simulated data to reflect real-world scenarios with differing levels of confounding, sample size, and NCO confounding structures. We then estimated and compared subgroup-level treatment effects on the primary outcome and NCOs across settings with and without unmeasured confounding. When conditional exchangeability was violated, causal forest and X-learner models failed to recover true treatment effect heterogeneity and, in some cases, falsely indicated heterogeneity when there was none. NCOs successfully identified subgroups affected by unmeasured confounding. Even when NCOs did not perfectly satisfy its ideal assumptions, it remained informative, flagging potential bias in subgroup level estimates, though not always pinpointing the subgroup with the largest confounding. Violations of conditional exchangeability substantially limit the validity of ITE estimates from causal ML models in routinely collected observational data. NCOs serve a useful empirical diagnostic tool for detecting subgroup-specific unmeasured confounding and should be incorporated into causal ML workflows to support the credibility of individualized inference.

Janick Weberpals, Pamela A. Shaw, Kueiyu Joshua Lin et al.

Multiple imputation (MI) models can be improved by including auxiliary covariates (AC), but their performance in high-dimensional data is not well understood. We aimed to develop and compare high-dimensional MI (HDMI) approaches using structured and natural language processing (NLP)-derived AC in studies with partially observed confounders. We conducted a plasmode simulation study using data from opioid vs. non-steroidal anti-inflammatory drug (NSAID) initiators (X) with observed serum creatinine labs (Z2) and time-to-acute kidney injury as outcome. We simulated 100 cohorts with a null treatment effect, including X, Z2, atrial fibrillation (U), and 13 other investigator-derived confounders (Z1) in the outcome generation. We then imposed missingness (MZ2) on 50% of Z2 measurements as a function of Z2 and U and created different HDMI candidate AC using structured and NLP-derived features. We mimicked scenarios where U was unobserved by omitting it from all AC candidate sets. Using LASSO, we data-adaptively selected HDMI covariates associated with Z2 and MZ2 for MI, and with U to include in propensity score models. The treatment effect was estimated following propensity score matching in MI datasets and we benchmarked HDMI approaches against a baseline imputation and complete case analysis with Z1 only. HDMI using claims data showed the lowest bias (0.072). Combining claims and sentence embeddings led to an improvement in the efficiency displaying the lowest root-mean-squared-error (0.173) and coverage (94%). NLP-derived AC alone did not perform better than baseline MI. HDMI approaches may decrease bias in studies with partially observed confounders where missingness depends on unobserved factors.