Citations

Abstract Objective The objective of the Strategic Health IT Advanced Research Project area four (SHARPn) was to develop open-source tools that could be used for the normalization of electronic health record (EHR) data for secondary use—specifically, for high throughput phenotyping. We describe the role of Intermountain Healthcare’s Clinical Element Models ([CEMs] Intermountain Healthcare Health Services, Inc, Salt Lake City, Utah) as normalization “targets” within the project. Materials and Methods Intermountain’s CEMs were either repurposed or created for the SHARPn project. A CEM describes “valid” structure and semantics for a particular kind of clinical data. CEMs are expressed in a computable syntax that can be compiled into implementation artifacts. The modeling team and SHARPn colleagues agilely gathered requirements and developed and refined models. Results Twenty-eight “statement” models (analogous to “classes”) and numerous “component” CEMs and their associated terminology were repurposed or developed to satisfy SHARPn high throughput phenotyping requirements. Model (structural) mappings and terminology (semantic) mappings were also created. Source data instances were normalized to CEM-conformant data and stored in CEM instance databases. A model browser and request site were built to facilitate the development. Discussion The modeling efforts demonstrated the need to address context differences and granularity choices and highlighted the inevitability of iso-semantic models. The need for content expertise and “intelligent” content tooling was also underscored. We discuss scalability and sustainability expectations for a CEM-based approach and describe the place of CEMs relative to other current efforts. Conclusions The SHARPn effort demonstrated the normalization and secondary use of EHR data. CEMs proved capable of capturing data originating from a variety of sources within the normalization pipeline and serving as suitable normalization targets.

Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus ( PKD1 versus PKD2 ). Recent studies identified nontruncating PKD1 mutations in approximately 30% of patients who underwent comprehensive mutation screening, but the clinical significance of these mutations is not well defined. We examined the genotype-renal function correlation in a prospective cohort of 220 unrelated ADPKD families ascertained through probands with serum creatinine ≤1.4 mg/dl at recruitment. We screened these families for PKD1 and PKD2 mutations and reviewed the clinical outcomes of the probands and affected family members. Height–adjusted total kidney volume (htTKV) was obtained in 161 affected subjects. Multivariate Cox proportional hazard modeling for renal and patient survival was performed in 707 affected probands and family members. Overall, we identified pathogenic mutations in 84.5% of our families, in which the prevalence of PKD1 truncating, PKD1 in–frame insertion/deletion, PKD1 nontruncating, and PKD2 mutations was 38.3%, 4.3%, 27.1%, and 30.3%, respectively. Compared with patients with PKD1 truncating mutations, patients with PKD1 in–frame insertion/deletion, PKD1 nontruncating, or PKD2 mutations have smaller htTKV and reduced risks (hazard ratio [95% confidence interval]) of ESRD (0.35 [0.14 to 0.91], 0.10 [0.05 to 0.18], and 0.03 [0.01 to 0.05], respectively) and death (0.31 [0.11 to 0.87], 0.20 [0.11 to 0.38], and 0.18 [0.11 to 0.31], respectively). Refined genotype-renal disease correlation coupled with targeted next generation sequencing of PKD1 and PKD2 may provide useful clinical prognostication for ADPKD.

Significance Our study not only reveals a novel role of peroxisome proliferator-activated receptor δ (PPARδ) in colonic inflammation and colitis-associated tumorigenesis, but also provides some rationale for development of PPARδ antagonists as new therapeutic agents in the treatment of inflammatory bowel disease and colitis-associated colorectal cancer. Moreover, our findings indicate that prostaglandin E 2 generated by chronic inflammation is a crucial mediator connecting chronic inflammation and colorectal carcinogenesis.

Drug-associated cues can elicit relapse to drug seeking after abstinence. Studies with extinction–reinstatement models implicate dopamine (DA) in the nucleus accumbens shell (NAshell) and dorsolateral caudate-putamen (dlCPu) in cocaine seeking. However, less is known about their roles in cue-induced opiate seeking after prolonged abstinence. Using a morphine self-administration and abstinence–relapse model, we explored the roles of NAshell and dlCPu DA and the D1/D2-like receptor mechanisms underlying morphine rewarding and/or seeking. Acquisition of morphine self-administration was examined following 6-Hydroxydopamine hydrobromide (6-OHDA) lesions of the NAshell and dlCPu. For morphine seeking, rats underwent 3 weeks’ morphine self-administration followed by 3 weeks’ abstinence from morphine and the training environment. Prior to testing, 6-OHDA, D1 antagonist SCH23390, or D2 antagonist eticlopride was locally injected; then rats were exposed to morphine-associated contextual and discrete cues. Results show that acquisition of morphine self-administration was inhibited by NAshell (not dlCPu) lesions, while morphine seeking was attenuated by lesions of either region, by D1 (not D2) receptor blockade in NAshell, or by blockade of either D1 or D2 receptors in dlCPu. These data indicate a critical role of dopaminergic transmission in the NAshell (via D1-like receptors) and dlCPu (via D1- and D2-like receptors) in morphine seeking after prolonged abstinence.