Citations

AbstractBackgroundAlthough the process of reclassification of a variant of uncertain significance can be complex, they are commonly detected through molecular testing. It often takes years before enough clinical data are acquired, and it can be costly and time‐consuming to perform functional analysis of a single variant. It is important that other tools are developed to aid in clarifying how a specific genetic variant impacts a protein's function, and ultimately the health of the patient.MethodsTwo more newly characterized, suspected pathogenic variants in NBN and PTEN were analyzed through personalized protein modeling. Comparisons between the wild‐type and altered protein were studied using simulations, genomic exome analysis, and clinic study.ResultsModeling of the new NBN and PTEN protein structures suggested loss of essential domains important for normal enzymatic function for these personalized genomic examples which matched the clinical findings.ConclusionThe defects detected through modeling were consistent with the expected clinical effect. Personalized protein modeling is another tool for determination of correct variant classification, which can become further useful through construction of deposition archive.

AbstractParenteral nutrition (PN) is a complex therapeutic modality provided to neonates, children, and adults for various indications. Surveys have shown that current electronic health record (EHR) systems are in need of functionality enhancement for safe and optimal delivery of PN. This is a consensus statement from the American Society for Parenteral and Enteral Nutrition, the Academy of Nutrition and Dietetics, and the American Society of Health‐System Pharmacists outlining some of the key challenges to prescribing, order review/verification, compounding, and administration of PN using EHRs today and is a call to action for clinicians and vendors to optimize their EHRs regarding the PN build and workflow.

Abstract Appropriate utilization of clinical laboratory services is important for patient care and requires institutional stewardship. Clinical laboratory stewardship programs are dedicated to improving the ordering, retrieval, and interpretation of appropriate laboratory tests. In addition, these programs focus on developing, maintaining, and improving systems to provide proper financial coverage for medically necessary testing. Overall, clinical laboratory stewardship programs help clinicians improve the quality of patient care while reducing costs to patients, hospitals, and health systems. This document, which was created by a new multiinstitutional committee interested in promoting and formalizing laboratory stewardship, summarizes core elements of successful hospital-based clinical laboratory stewardship programs. The core elements will also be helpful for independent commercial clinical laboratories.

Abstract Electronic health record (EHR) algorithms for defining patient cohorts are commonly shared as free-text descriptions that require human intervention both to interpret and implement. We developed the Phenotype Execution and Modeling Architecture (PhEMA, http://projectphema.org) to author and execute standardized computable phenotype algorithms. With PhEMA, we converted an algorithm for benign prostatic hyperplasia, developed for the electronic Medical Records and Genomics network (eMERGE), into a standards-based computable format. Eight sites (7 within eMERGE) received the computable algorithm, and 6 successfully executed it against local data warehouses and/or i2b2 instances. Blinded random chart review of cases selected by the computable algorithm shows PPV ≥90%, and 3 out of 5 sites had >90% overlap of selected cases when comparing the computable algorithm to their original eMERGE implementation. This case study demonstrates potential use of PhEMA computable representations to automate phenotyping across different EHR systems, but also highlights some ongoing challenges.

The highly polymorphic human leukocyte antigen (HLA) class I molecules present peptide antigens to CD8+ T cells, inducing immunity against infections and cancers. Quality control mediated by peptide loading complex (PLC) components is expected to ensure the cell surface expression of stable peptide-HLA class I complexes. This is exemplified by HLA-B*08:01 in primary human lymphocytes, with both expression level and half-life at the high end of the measured HLA-B expression and stability hierarchies. Conversely, low expression on lymphocytes is measured for three HLA-B allotypes that bind peptides with proline at position 2, which are disfavored by the transporter associated with antigen processing. Surprisingly, these lymphocyte-specific expression and stability differences become reversed or altered in monocytes, which display larger intracellular pools of HLA class I than lymphocytes. Together, the findings indicate that allele and cell-dependent variations in antigen acquisition pathways influence HLA-B surface expression levels, half-lives and receptivity to exogenous antigens.

Key Points Using the largest set of patients with newly diagnosed myeloma, we identified 63 mutated driver genes. We identified oncogenic dependencies, particularly relating to primary translocations, indicating a nonrandom accumulation of genetic hits.

Background Ideal cardiovascular health metrics (defined by the American Heart Association Life's Simple 7 [LS7]) are suboptimal among blacks, which results in high risk of cardiovascular disease. We examined the association of multiple stressors with LS7 components among blacks. Methods and Results Using a community‐based cohort of blacks (N=4383), we examined associations of chronic stress, minor stressors, major life events, and a cumulative stress score with LS7 components (smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting plasma glucose) and an LS7 composite score. Multivariable logistic regression assessed the odds of achieving intermediate/ideal levels of cardiovascular health adjusted for demographic, socioeconomic, behavioral, and biomedical factors. The LS7 components with the lowest percentages of intermediate/ideal cardiovascular health levels were diet (39%), body mass index (47%), and physical activity (51%). Higher chronic, minor, and cumulative stress scores were associated with decreased odds (odds ratio [OR]) of achieving intermediate/ideal levels for smoking (OR [95% confidence interval], 0.80 [0.73–0.88], 0.84 [0.75–0.94], and 0.81 [0.74–0.90], respectively). Participants with more major life events had decreased odds of achieving intermediate/ideal levels for smoking (OR, 0.84; 95% confidence interval, 0.76–0.92) and fasting plasma glucose (OR, 0.90; 95% confidence interval, 0.82–0.98). Those with higher scores for minor stressors and major life events were less likely to achieve intermediate or ideal LS7 composite scores (OR [95% confidence interval], 0.89 [0.81–0.97] and 0.91 [0.84–0.98], respectively). Conclusions Blacks with higher levels of multiple stress measures are less likely to achieve intermediate or ideal levels of overall cardiovascular health (LS7 composite score), specific behaviors (smoking), and biological factors (fasting plasma glucose).