The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.

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This study aimed to determine whether patients with statin-induced myopathy could be identified using the United Kingdom Clinical Practice Research Datalink, whether DNA could be obtained, and whether previously reported associations of statin myopathy with the SLCO1B1 c.521T>C and COQ2 rs4693075 polymorphisms could be replicated. Seventy-seven statin-induced myopathy patients (serum creatine phosphokinase (CPK) > 4× upper limit of normal (ULN)) and 372 statin-tolerant controls were identified and recruited. Multiple logistic regression analysis showed the SLCO1B1 c.521T>C single-nucleotide polymorphism to be a significant risk factor (P = 0.009), with an odds ratio (OR) per variant allele of 2.06 (1.32–3.15) for all myopathy and 4.09 (2.06–8.16) for severe myopathy (CPK > 10× ULN, and/or rhabdomyolysis; n = 23). COQ2 rs4693075 was not associated with myopathy. Meta-analysis showed an association between c.521C>T and simvastatin-induced myopathy, although power for other statins was limited. Our data replicate the association of SLCO1B1 variants with statin-induced myopathy. Furthermore, we demonstrate how electronic medical records provide a time- and cost-efficient means of recruiting patients with severe adverse drug reactions for pharmacogenetic studies.

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BackgroundThere is currently limited evidence regarding the extent Real World Evidence (RWE) has directly impacted the health and social care systems. The aim of this review is to identify national guidelines or guidances published in England from 2000 onwards which have referenced studies using the governmental primary care data provider the Clinical Practice Research Datalink (CPRD).MethodsThe methodology recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed. Four databases were searched and documents of interest were identified through a search algorithm containing keywords relevant to CPRD. A search diary was maintained with the inclusion/exclusion decisions which were performed by two independent reviewers.ResultsTwenty-five guidance documents were included in the final review (following screening and assessment for eligibility), referencing 43 different CPRD/GPRD studies, all published since 2007. The documents covered 12 disease areas, with the majority (N =7) relevant to diseases of the Central Nervous system (CNS). The 43 studies provided evidence of disease epidemiology, incidence/prevalence, pharmacoepidemiology, pharmacovigilance and health utilisation.ConclusionsA slow uptake of RWE in clinical and therapeutic guidelines (as provided by UK governmental structures) was noticed. However, there seems to be an increasing trend in the use of healthcare system data to inform clinical practice, especially as the real world validity of clinical trials is being questioned. In order to accommodate this increasing demand and meet the paradigm shift expected, organisations need to work together to enable or improve data access, undertake translational and relevant research and establish sources of reliable evidence.

Limited data exist to guide physicians in the cost-effective treatment of acute exacerbation of chronic bronchitis (AECB). Therefore, the main objective of this study was to determine the antimicrobial efficacy and related costs for patients with AECB. A retrospective review of 60 outpatient medical records with a diagnosis of chronic obstructive pulmonary disease (COPD) and chronic bronchitis episodes from a pulmonary clinic of a teaching institution was undertaken. The participating patients had a total of 224 episodes of AECB requiring antibiotic treatment. Before review, empirical antibiotic choices were divided into first-line (amoxycillin, co-trimoxazole, tetracyclines, erythromycin), second-line (cephradine, cefuroxime, cefaclor, cefprozil) and third-line (co-amoxiclav, azithromycin, ciprofloxacin) agents. Patients receiving first-line agents failed significantly more frequently than third-line agents (19% vs 7%, P < 0.05). Additionally, patients prescribed first-line agents were hospitalized significantly more often for AECB within 2 weeks of outpatient treatment as compared with patients prescribed third-line agents (18.0% vs 5.3% third-line agents; P < 0.02). Time between subsequent AECB episodes requiring treatment was significantly longer for patients receiving third-line agents compared with first-line and second-line agents (P < 0.005). Pharmacy costs were lowest with first-line agents (first-line US$10.30 +/- 8.76; second-line US$24.45 +/- 25.65; third-line US$45.40 +/- 11.11; P < 0.0001), but third-line agents showed a trend towards lower mean total costs of AECB treatment (first-line US$942 +/- 2173; second-line, US$563 +/- 2296; third-line, US$542 +/- 1946). The use of third-line antimicrobials, co-amoxiclav, ciprofloxacin or azithromycin, significantly reduced the failure rate and need for hospitalization, prolonged the time between AECB episodes, and showed a lower total cost for the management of AECB. Prospective studies are needed to confirm these findings.

Summary Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein ( SRCAP ) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo ) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as “non-FLHS SRCAP -related NDD.” All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP , there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

BackgroundThe Alere point-of-care (POC) Pima™ CD4 analyzer allows for decentralized testing and expansion to testing antiretroviral therapy (ART) eligibility. A consortium conducted a pooled multi-data technical performance analysis of the Pima CD4.MethodsPrimary data (11,803 paired observations) comprised 22 independent studies between 2009–2012 from the Caribbean, Asia, Sub-Saharan Africa, USA and Europe, using 6 laboratory-based reference technologies. Data were analyzed as categorical (including binary) and numerical (absolute) observations using a bivariate and/or univariate random effects model when appropriate.ResultsAt a median reference CD4 of 383 cells/μl the mean Pima CD4 bias is -23 cells/μl (average bias across all CD4 ranges is 10 % for venous and 15 % for capillary testing). Sensitivity of the Pima CD4 is 93 % (95 % confidence interval [CI] 91.4 % - 94.9 %) at 350 cells/μl and 96 % (CI 95.2 % - 96.9 %) at 500 cells/μl, with no significant difference between venous and capillary testing. Sensitivity reduced to 86 % (CI 82 % - 89 %) at 100 cells/μl (for Cryptococcal antigen (CrAg) screening), with a significant difference between venous (88 %, CI: 85 % - 91 %) and capillary (79 %, CI: 73 % - 84 %) testing. Total CD4 misclassification is 2.3 % cases at 100 cells/μl, 11.0 % at 350 cells/μl and 9.5 % at 500 cells/μl, due to higher false positive rates which resulted in more patients identified for treatment. This increased by 1.2 %, 2.8 % and 1.8 %, respectively, for capillary testing. There was no difference in Pima CD4 misclassification between the meta-analysis data and a population subset of HIV+ ART naïve individuals, nor in misclassification among operator cadres. The Pima CD4 was most similar to Beckman Coulter PanLeucogated CD4, Becton Dickinson FACSCalibur and FACSCount, and less similar to Partec CyFlow reference technologies.ConclusionsThe Pima CD4 may be recommended using venous-derived specimens for screening (100 cells/μl) for reflex CrAg screening and for HIV ART eligibility at 350 cells/μl and 500 cells/μl thresholds using both capillary and venous derived specimens. These meta-analysis findings add to the knowledge of acceptance criteria of the Pima CD4 and future POC tests, but implementation and impact will require full costing analysis.