High performance implementation of the hierarchical likelihood for generalized linear mixed models: an application to estimate the potassium reference range in massive electronic health records datasets.

BACKGROUND: Converting electronic health record (EHR) entries to useful clinical inferences requires one to address the poor scalability of existing implementations of Generalized Linear Mixed Models (GLMM) for repeated measures. The major computational bottleneck concerns the numerical evaluation of multivariable integrals, which even for the simplest EHR analyses may involve millions of dimensions (one for each patient). The hierarchical likelihood (h-lik) approach to GLMMs is a methodologically rigorous framework for the estimation of GLMMs that is based on the Laplace Approximation (LA), which replaces integration with numerical optimization, and thus scales very well with dimensionality. METHODS: We present a high-performance, direct implementation of the h-lik for GLMMs in the R package TMB. Using this approach, we examined the relation of repeated serum potassium measurements and survival in the Cerner Real World Data (CRWD) EHR database. Analyzing this data requires the evaluation of an integral in over 3 million dimensions, putting this problem beyond the reach of conventional approaches. We also assessed the scalability and accuracy of LA in smaller samples of 1 and 10% size of the full dataset that were analyzed via the a) original, interconnected Generalized Linear Models (iGLM), approach to h-lik, b) Adaptive Gaussian Hermite (AGH) and c) the gold standard for multivariate integration Markov Chain Monte Carlo (MCMC). RESULTS: Random effects estimates generated by the LA were within 10% of the values obtained by the iGLMs, AGH and MCMC techniques. The H-lik approach was 4-30 times faster than AGH and nearly 800 times faster than MCMC. The major clinical inferences in this problem are the establishment of the non-linear relationship between the potassium level and the risk of mortality, as well as estimates of the individual and health care facility sources of variations for mortality risk in CRWD. CONCLUSIONS: We found that the direct implementation of the h-lik offers a computationally efficient, numerically accurate approach for the analysis of extremely large, real world repeated measures data via the h-lik approach to GLMMs. The clinical inference from our analysis may guide choices of treatment thresholds for treating potassium disorders in the clinic.

Cognitive assessment in a predominantly Hispanic and Native American population in New Mexico and its association with kidney transplant wait-listing.

The association between cognitive function and the likelihood of kidney transplant (KT) wait-listing, especially in minority populations, has not been clearly delineated. We performed a retrospective review of our pre-KT patients, who consist mainly of Hispanics and Native Americans, over a 16-month period. We collected data on baseline demographics and the Montreal Cognitive Assessment (MoCA) score, at the initial KT evaluation. We defined cognitive impairment as MoCA scores of <24. We constructed linear regression models to identify associations between baseline characteristics with MoCA scores and used Cox proportional hazards models to assess associations between MoCA score and KT wait-listing. During the study period, 154 patients completed the MoCA during their initial evaluation. Mean (standard deviation) MoCA scores were 23.9 (4.6), with 58 (38%) participants scoring <24. Advanced age, lower education and being on dialysis were associated with lower MoCA scores. For every one-point increase in MoCA, the likelihood of being wait-listed increased 1.10-fold (95% CI 1.01-1.19, P = .022). Being Native American and having kidney disease due to diabetes or hypertension were associated with longer time to wait-listing. Cognitive impairment was common in our pre-KT patients and was associated with a lower likelihood of KT wait-listing.