Electronic medical records are emerging as a major source of data for clinical and translational research studies, although phenotypes of interest need to be accurately defined first. This article provides an overview of how to develop a phenotype algorithm from electronic medical records, incorporating modern informatics and biostatistics methods.

Introduction Vitamin D may have an immunological role in Crohn’s disease (CD) and ulcerative colitis (UC). Retrospective studies suggested a weak association between vitamin D status and disease activity but have significant limitations. Methods Using a multi-institution inflammatory bowel disease (IBD) cohort, we identified all CD and UC patients who had at least one measured plasma 25-hydroxy vitamin D [25(OH)D]. Plasma 25(OH)D was considered sufficient at levels ≥ 30ng/mL. Logistic regression models adjusting for potential confounders were used to identify impact of measured plasma 25(OH)D on subsequent risk of IBD-related surgery or hospitalization. In a subset of patients where multiple measures of 25(OH)D were available, we examined impact of normalization of vitamin D status on study outcomes. Results Our study included 3,217 patients (55% CD, mean age 49 yrs). The median lowest plasma 25(OH)D was 26ng/ml (IQR 17–35ng/ml). In CD, on multivariable analysis, plasma 25(OH)D < 20ng/ml was associated with an increased risk of surgery (OR 1.76 (1.24 – 2.51) and IBD-related hospitalization (OR 2.07, 95% CI 1.59 – 2.68) compared to those with 25(OH)D ≥ 30ng/ml. Similar estimates were also seen for UC. Furthermore, CD patients who had initial levels < 30ng/ml but subsequently normalized their 25(OH)D had a reduced likelihood of surgery (OR 0.56, 95% CI 0.32 – 0.98) compared to those who remained deficient. Conclusion Low plasma 25(OH)D is associated with increased risk of surgery and hospitalizations in both CD and UC and normalization of 25(OH)D status is associated with a reduction in the risk of CD-related surgery.

(1) but not all hallucinogens (2, 3) and is the target of a number of commonly prescribed therapeutic agents including atypical antipsychotics, antidepressants, and anxiolytics (4, 5). As with other G protein-coupled receptors (GPCRs) (6 -8), elucidating the regulatory mechanisms for 5-HT 2A receptor signaling and trafficking provides important insights into the therapeutic mechanisms of drugs that target the 5-HT 2A receptor and has implications for the rational design of novel medications (5, 6).The 5-HT 2A receptor, the most abundant serotonin receptor in the cerebral cortex, is enriched in dendritic shafts and, to a lesser extent, asymmetric synapses and dendritic spines of pyramidal neurons primarily from Layers IV and V (9 -13). The last four amino acids (VSCV) of the carboxyl terminus of the 5-HT 2A receptor constitute a canonical Type I PDZ-binding domain (X-Ser/Thr-X-⌽) (14). The PDZ-binding domain is located at the carboxyl terminus of a variety of proteins including many GPCRs and is known to associate with PSD-95/Discslarge/ZO-1 (PDZ) domain-containing proteins of which postsynaptic density 95 (PSD-95, also known as synapse-associated protein 90 or SAP-90, is a prototypic member (15, 16). These multi-domain molecules not only target and provide scaffolds for protein-protein interactions but can also modulate the functions of ion channels and receptors with which they associate (16 -20). The disruption of the association between PDZ proteins and their targets contributes to the pathogenesis of a number of human diseases (16,21,22), most probably because of the failure of PDZ proteins to appropriately target and modulate the actions of the associated proteins. Na ϩ /H ϩ exchanger regulatory factor (NHE-RF) was the first PDZ domain-containing protein that was reported to modulate the function of a GPCR (e.g. the ␤ 2 -adrenergic receptor (␤ 2 -AR)) (23). Subsequently, PSD-95 was found to associate with and inhibit the internalization of ␤ 1 -ARs and to facilitate the interaction between the ␤ 1 -AR and the N-methyl-D-aspartate ionotropic glutamate receptor (24,25). Among the 5-HT 2 class of serotonin receptors, a multi-PDZ domain-containing protein, MUPP1, associates with 5-HT 2C receptors in vitro and in vivo (26). MUPP1 has also been predicted to interact with both the 5-HT 2A and the 5-HT 2B receptor based on its ability to bind to purified COOH-terminal fusion proteins of both receptors in vitro (26). Furthermore, a proteomic approach has recently identified PSD-95 as a component of a multi-protein complex that associates with the 5-HT 2C receptor in vivo (27). PSD-95, similar to the 5-HT 2A receptor, is enriched in asymmetric synapses and dendritic spines of cortical pyramidal neurons (28,29) and is thus predicted to interact with 5-HT 2A receptors. The functional significance of any association between PDZ proteins and 5-HT receptors is unknown because none has been previously reported.Therefore, we set out to investigate whether PSD-95 interacts with and regulates 5-HT 2A receptors. A combination...