Predicting residents' performance: A prospective study

BACKGROUND: Objective criteria for predicting residents' performance do not exist. The purpose of this study was to test the hypothesis that global assessment by an intern selection committee (ISC) would correlate with the future performance of residents. METHODS: A prospective study of 277 residents between 1992 and 1999. Global assessment at the time of interview was compared to subsequent clinical (assessed by chief residents) and cognitive performance (assessed by the American Board of Pediatrics in-service training examination). RESULTS: ISC ratings correlated significantly with clinical performance at 24 and 36 months of training (r = 0.58, P < .001; and r = 0.60, P < .001 respectively). ISC ratings also correlated significantly with in-service exam scores in the 1(st), 2(nd), and 3(rd) years of training (r = 0.35, P = .0016; r = 0.39, P = 0.0003; r = 0.50, P = 0.005 respectively). CONCLUSIONS: Global assessment by an ISC predicted residents' clinical and cognitive performances

Psychometric precision in phenotype definition is a useful step in molecular genetic investigation of psychiatric disorders

Affective disorders are highly heritable, but few genetic risk variants have been consistently replicated in molecular genetic association studies. The common method of defining psychiatric phenotypes in molecular genetic research is either a summation of symptom scores or binary threshold score representing the risk of diagnosis. Psychometric latent variable methods can improve the precision of psychiatric phenotypes, especially when the data structure is not straightforward. Using data from the British 1946 birth cohort, we compared summary scores with psychometric modeling based on the General Health Questionnaire (GHQ-28) scale for affective symptoms in an association analysis of 27 candidate genes (249 single-nucleotide polymorphisms (SNPs)). The psychometric method utilized a bi-factor model that partitioned the phenotype variances into five orthogonal latent variable factors, in accordance with the multidimensional data structure of the GHQ-28 involving somatic, social, anxiety and depression domains. Results showed that, compared with the summation approach, the affective symptoms defined by the bi-factor psychometric model had a higher number of associated SNPs of larger effect sizes. These results suggest that psychometrically defined mental health phenotypes can reflect the dimensions of complex phenotypes better than summation scores, and therefore offer a useful approach in genetic association investigations

Discourses of student orientation to medical education programs

Background: Although medical students’ initial orientation is an important point of transition in medical education, there is a paucity of literature on the subject and major variations in the ways that different institutions orient incoming medical students to their programs. Methods: We conducted a discourse analysis of medical education orientation in the literature and on data from a survey of peer institutions’ approaches to orientation. Results: These two discourses of orientation had clear similarities, in particular, the critical role of ceremony and symbols, and the focus on developing professionalism and physician identities. There were also differences between them, in particular, in the way that the discourse in the literature focused on the symbolic and professional aspects of orientation; something we have called ‘cultural orientation’. Meanwhile, those who were responsible for orientation in their own institutions tended to focus on the practical and social dimensions. Conclusion: By examining how orientation has been described and discussed, we identify three domains of orientation: cultural, social, and practical. These domains are relatively distinct in terms of the activities associated with them, and in terms of who is involved in organizing and running these activities. We also describe orientation as a liminal activity system on the threshold of medical school where incoming students initially cross into the profession. Interestingly, this state of ambiguity also extends to the scholarship of orientation with only some of its aspects attracting formal enquiry, even though there is a growing interest in transitions in medical education as a whole. We hope, therefore, that this study can help to legitimize enquiry into orientation in all its forms and that it can begin to situate the role of orientation more firmly within the firmament of medical education practice and research

The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD

A systematic review of associations between functional MRI activity and polygenic risk for schizophrenia and bipolar disorder

Genetic factors account for up to 80% of the liability for schizophrenia (SCZ) and bipolar disorder (BD). Genome-wide association studies have successfully identified several genes associated with increased risk for both disorders. This has allowed researchers to model the aggregate effect of genes associated with disease status and create a polygenic risk score (PGRS) for each individual. The interest in imaging genetics using PGRS has grown in recent years, with several studies now published. We have conducted a systematic review to examine the effects of PGRS of SCZ, BD and cross psychiatric disorders on brain function and connectivity using fMRI data. Results indicate that the effect of genetic load for SCZ and BD on brain function affects task-related recruitment, with frontal areas having a more prominent role, independent of task. Additionally, the results suggest that the polygenic architecture of psychotic disorders is not regionally confined but impacts on the task-dependent recruitment of multiple brain regions. Future imaging genetics studies with large samples, especially population studies, would be uniquely informative in mapping the spatial distribution of the genetic risk to psychiatric disorders on brain processes during various cognitive tasks and may lead to the discovery of biological pathways that could be crucial in mediating the link between genetic factors and alterations in brain networks

Skp is a multivalent chaperone of outer membrane proteins

The trimeric chaperone Skp sequesters outer-membrane proteins (OMPs) within a hydrophobic cage, thereby preventing their aggregation during transport across the periplasm in Gram-negative bacteria. Here, we studied the interaction between Escherichia coli Skp and five OMPs of varying size. Investigations of the kinetics of OMP folding revealed that higher Skp/OMP ratios are required to prevent the folding of 16-stranded OMPs compared with their 8-stranded counterparts. Ion mobility spectrometry–mass spectrometry (IMS–MS) data, computer modeling and molecular dynamics simulations provided evidence that 10- to 16-stranded OMPs are encapsulated within an expanded Skp substrate cage. For OMPs that cannot be fully accommodated in the expanded cavity, sequestration is achieved by binding of an additional Skp trimer. The results suggest a new mechanism for Skp chaperone activity involving the coordination of multiple copies of Skp in protecting a single substrate from aggregation

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes