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Abstract Background Evidence of genetic association between the NRG1 (Neuregulin-1) gene and schizophrenia is now well-documented. Furthermore, several recent reports suggest association between schizophrenia and single-nucleotide polymorphisms (SNPs) in ERBB4, one of the receptors for Neuregulin-1. In this study, we have extended the previously published associations by investigating the involvement of all eight genes from the ERBB and NRG families for association with schizophrenia. Methods Eight genes from the ERBB and NRG families were tested for association to schizophrenia using a collection of 396 cases and 1,342 blood bank controls ascertained from Aberdeen, UK. A total of 365 SNPs were tested. Association testing of both alleles and genotypes was carried out using the fast Fisher's Exact Test (FET). To understand better the nature of the associations, all pairs of SNPs separated by ≥ 0.5 cM with at least nominal evidence of association (P < 0.10) were tested for evidence of pairwise interaction by logistic regression analysis. Results 42 out of 365 tested SNPs in the eight genes from the ERBB and NRG gene families were significantly associated with schizophrenia (P < 0.05). Associated SNPs were located in ERBB4 and NRG1, confirming earlier reports. However, novel associations were also seen in NRG2, NRG3 and EGFR. In pairwise interaction tests, clear evidence of gene-gene interaction was detected for NRG1-NRG2, NRG1-NRG3 and EGFR-NRG2, and suggestive evidence was also seen for ERBB4-NRG1, ERBB4-NRG2, ERBB4-NRG3 and ERBB4-ERBB2. Evidence of intragenic interaction was seen for SNPs in ERBB4. Conclusion These new findings suggest that observed associations between NRG1 and schizophrenia may be mediated through functional interaction not just with ERBB4, but with other members of the NRG and ERBB families. There is evidence that genetic interaction among these loci may increase susceptibility to schizophrenia.

Confounding by indication is a key challenge for pharmacoepidemiologists. Although self-controlled study designs address time-invariant confounding, indications sometimes vary over time. For example, infection might act as a time-varying confounder in a study of antibiotics and uveitis, because it is time-limited and a direct cause both of receiving antibiotics and uveitis. Methods for incorporating active comparators in self-controlled studies to address such time-varying confounding by indication have only recently been developed. In this paper we formalize these methods, and provide a detailed description for how the active comparator rate ratio can be derived in a self-controlled case series (SCCS): either by explicitly comparing the regression coefficients for a drug of interest and an active comparator under certain circumstances using a simple ratio approach, or through the use of a nested regression model. The approaches are compared in two case studies, one examining the association between thiazolidinediones and fractures, and one examining the association between fluoroquinolones and uveitis using the UK Clinical Practice Research DataLink. Finally, we provide recommendations for the use of these methods, which we hope will support the design, execution and interpretation of SCCS using active comparators and thereby increase the robustness of pharmacoepidemiological studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Purpose: Improved hypereosinophilic syndrome (HES) ascertainment in electronic health record (EHR) databases may improve disease understanding and management. An algorithm to ascertain and characterize this rare condition was therefore developed and validated., Methods: Using the UK clinical practice research datalink (CPRD)-Aurum database linked to the hospital episode statistics database (Admitted Patient Care data) from Jan 2012 to June 2019, this cross-sectional study ascertained patients with a specific HES code (index). Patients with HES were matched (age, sex and index date) 1:29 with a non-HES cohort. An algorithm was developed by identifying pre-defined variables differing between cohorts; model-fitting using Firth logistic regression and statistical determination of the top-five performing models; and internal validation using Leave-One-Out Cross Validation. Final model sensitivity and specificity were determined at an 80% probability threshold., Results: The HES and non-HES cohorts included 88 and 2552 patients, respectively; 270 models with four variables each (treatment used for HES, asthma code, white blood cell condition code, and blood eosinophil count [BEC] code) plus age and sex variables were tested. Of the top five models, the sensitivity model performed best (sensitivity, 69% [95% CI: 59%, 79%]; specificity, >99%). The strongest predictors of HES versus non-HES cases (odds >1000 times greater) were an ICD-10 code for white blood cell disorders and a BEC ≥1500 cells/μL in the 24 months pre-index., Conclusions: Using a combination of medical codes, prescribed treatments data and laboratory results, the algorithm can help ascertain patients with HES from EHR databases; this approach may be useful for other rare diseases., (© 2023 GSK. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Several Bayesian methods have been proposed to borrow information dynamically from historical controls in clinical trials. In this note, we identify key features of the relationship between the first method proposed, the bias-variance method, which is strongly related to the commensurate prior approach, and a more recent and widely used approach called robust mixture priors (RMP). We focus on the two key terms that need to be chosen to define the RMP, namely $w$, the prior probability that the new trial differs systematically from the historical trial, and $s&#95;v^2$, the variance of the vague component of the RMP. The relationship with Pocock's prior reveals that different combinations of these two terms can express similar prior beliefs about the amount of information provided by the historical data. This demonstrates the value of fixing $s&#95;v^2$, e.g., so the vague component is "worth one subject." Prior belief about the relevance of the historical data is then driven by a single value, the prespecified weight $w$., (© The Author 2021. Published by Oxford University Press.)

Objectives: Diabetes self-care may become increasingly challenging as cognition declines. We sought to characterize glycated hemoglobin A 1c (HbA 1c ) trajectories, markers of diabetes-related management, health care utilization, and mortality in people with preexisting type 2 diabetes (T2D) with and without dementia and based on the extent of cognitive impairment at the time of dementia diagnosis., Design: Retrospective matched cohort study., Setting and Participants: Using a linkage between a primary care (Lambeth DataNet) and a secondary mental healthcare database, up to 5 individuals aged ≥65 y with preexisting T2D without dementia were matched to each individual with dementia based on age, sex, and general practice., Methods: Comparisons were made for HbA 1c trajectories (linear mixed effects models), markers of diabetes-related management and severity at dementia diagnosis (logistic regression), mortality (Cox regression), and health care utilization (multilevel mixed effects binomial regression)., Results: In 725 incident dementia and 3154 matched comparators, HbA 1c trajectories differed by dementia status; HbA 1c increased over time for mild dementia and non-dementia, but the increase was greater in the mild dementia group; for those with moderate-severe dementia, HbA 1c decreased over time. Despite individuals with dementia having increased health care utilization around the time of dementia diagnosis, they were less likely to have had routine diabetes-related management. Patients with dementia had a higher prevalence of macrovascular complications and diabetes foot morbidity at dementia diagnosis and a higher mortality risk than those without dementia; these relationships were most marked in those with moderate-severe dementia., Conclusions and Implications: Our study has highlighted important differences in the monitoring, management, and control of diabetes in people with dementia. The effects of frailty and the extent of cognitive impairment on the ability to self-manage diabetes and on glycemic control may need to be considered in treatment guidelines and by primary care., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Skin fibrosis is a hallmark feature of systemic sclerosis. Skin biopsy transcriptomics and blister fluid proteomics give insight into the local environment of the skin. We have integrated these modalities with the aim of developing a surrogate for the modified Rodnan skin score (mRSS), using candidate genes and proteins from the skin and blister fluid as anchors to identify key analytes in the plasma., Methods: In this single-centre, prospective observational study at the Royal Free Campus, University College London, London, UK, transcriptional and proteomic analyses of blood and skin were performed in a cohort of patients with systemic sclerosis (n=52) and healthy controls (n=16). Weighted gene co-expression network analysis was used to explore the association of skin transcriptomics data, clinical traits, and blister fluid proteomic results. Candidate hub analytes were identified as those present in both blister and skin gene sets (modules), and which correlated with plasma (module membership >0·7 and gene significance >0·6). Hub analytes were confirmed using RNA transcript data obtained from skin biopsy samples from patients with early diffuse cutaneous systemic sclerosis at 12 months., Findings: We identified three modules in the skin, and two in blister fluid, which correlated with a diagnosis of early diffuse cutaneous systemic sclerosis. From these modules, 11 key hub analytes were identified, present in both skin and blister fluid modules, whose transcript and protein levels correlated with plasma protein concentrations, mRSS, and showed statistically significant correlation on repeat transcriptomic samples taken at 12 months. Multivariate analysis identified four plasma analytes as correlates of mRSS (COL4A1, COMP, SPON1, and TNC), which can be used to differentiate disease subtype., Interpretation: This unbiased approach has identified potential biological candidates that might be drivers of local skin pathogenesis in systemic sclerosis. By focusing on measurable analytes in the plasma, we generated a promising composite plasma protein biomarker that could be used for assessment of skin severity, case stratification, and as a potential outcome measure for clinical trials and practice. Once fully validated, the biomarker score could replace a clinical score such as the mRSS, which carries substantial variability., Funding: GlaxoSmithKline and UK Medical Research Council., Competing Interests: CPD reports consulting fees or honoraria from Janssen, GlaxoSmithKline, Roche, Boehringer Ingelheim, Sanofi, Galapagos, Inventiva, Corbus, Acceleron, Horizon, Gesynta, and ARXX Therapeutics; and from research grants to their institution from GlaxoSmithKline, ARXX Therapeutics, Servier, and Horizon Therapeutics. NW, SMF, YVT, JF, NG, EC, KN, and MAM are employees of GlaxoSmithKline. NG, EC, JF, NW, MAM, SMF, and KN are shareholders in GlaxoSmithKline. All other authors declare no competing interests, (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Background: The clinical context for using blood eosinophil (EOS) counts as treatment-response biomarkers in asthma and COPD requires better understanding of EOS distributions and ranges. We describe EOS distributions and ranges published in asthma, COPD, control (non-asthma/COPD) and general populations., Methods: We conducted a comprehensive literature review and meta-analysis of observational studies (January 2008 to November 2018) that included EOS counts in asthma, severe asthma, COPD, control and general populations. Excluded studies had total sample sizes <200, EOS as inclusion criterion, hospitalised population only and exclusively paediatric participants., Results: Overall, 91 eligible studies were identified, most had total-population-level data available: asthma (39 studies), severe asthma (12 studies), COPD (23 studies), control (seven studies) and general populations (14 studies); some articles reported data for multiple populations. Reported EOS distributions were right-skewed (seven studies). Reported median EOS counts ranged from 157-280 cells·µL -1 (asthma, 22 studies); 200-400 cells·µL -1 (severe asthma, eight studies); 150-183 cells·µL -1 (COPD, six studies); and 100-160 cells·µL -1 (controls, three studies); and 100-200 cells·µL -1 (general populations, six studies). The meta-analysis showed that observed variability was mostly between studies rather than within studies. Factors reportedly associated with higher blood EOS counts included current smoking, positive skin-prick test, elevated total IgE, comorbid allergic rhinitis, age ≤18 years, male sex, spirometric asthma/COPD diagnosis, metabolic syndrome and adiposity., Conclusion: EOS distribution and range varied by study population, and were affected by clinical factors including age, smoking history and comorbidities, which, regardless of severity, should be considered during treatment decision-making., Competing Interests: Conflict of interest: V.S. Benson reports employment by GlaxoSmithKline, and stock/share ownership in GlaxoSmithKline. Conflict of interest: S. Hartl reports unrestricted grants from AstraZeneca, GlaxoSmithKline, Böhringer Ingelheim, Menarini, Chiesi Farma, Pfizer, MSD, Air Liquide, Vivisol for the Ludwig Boltzmann Research Institute of Lung Health supporting the LEAD study. Conflict of interest: N. Barnes reports employment by GlaxoSmithKline, and stock/share ownership in GlaxoSmithKline. Conflict of interest: N. Galwey reports employment by GlaxoSmithKline, and stock/share ownership in GlaxoSmithKline. Conflict of interest: M.K. Van Dyke reports employment by GlaxoSmithKline, and stock/share ownership in GlaxoSmithKline. Conflict of interest: N. Kwon reports employment by GlaxoSmithKline, and stock/share ownership in GlaxoSmithKline., (Copyright ©The authors 2022.)

Objectives: Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodies METHODS: We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities., Results: Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis., Conclusions: Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To estimate the risk of dyskinesia and impulse control disorders (ICDs) in patients with Parkinson's disease (PD) prescribed ropinirole prolonged-release (R-PR) compared to those prescribed immediate-release dopamine agonists (IR-DA) as monotherapy., Methods: PD patients initiating R-PR or IR-DA as monotherapy between 2008 and 2013 were identified on the Clinical Practice Research Datalink. The cohorts were propensity score matched on a 1:1 basis. The incidence of dyskinesia and ICD in each treatment cohort and the incidence rate ratios were calculated. Adherence to medication and time to levodopa initiation were also evaluated., Results: We identified 341 patients in each treatment cohort after propensity score matching. The baseline characteristics were generally comparable. Dyskinesia incidence in R-PR and IR-DA cohorts was 2.98 (95% CI: 0.74-11.9) and 3.93 (95% CI: 0.98-15.7) per 1000 person-years, respectively (incidence rate ratio of R-PR vs ID-DA: 0.76, 95% CI: 0.11-5.38). Less than five cases of ICD were identified and all occurred in the IR-DA cohort. The patients in the R-PR cohort remained on treatment for a significantly longer duration than those in the IR-DA cohort (682 days vs 444 days; P < .0001) and had greater adherence to the medication. The median time to levodopa initiation was 417 days (IQR: 205-736) in R-PR vs 297 days (IQR: 111-552) in IR-DA cohort., Conclusions: The number of dyskinesia and ICD events was lower than expected, resulting in an underpowered study. A significantly longer persistence and greater adherence to medication was observed in patients receiving R-PR compared to IR-DA., (© 2020 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objective: To identify phenotypic factors associated with the Short Physical Performance Battery (SPPB) and its individual sub-tests: standing balance, 4‑meter gait speed (4mGS) and 5-repetition sit-to-stand (5STS)., Methods: The Evaluation of the Role of Inflammation in non-pulmonary disease manifestations in Chronic Airways disease (ERICA) study recruited adult participants with stable chronic obstructive pulmonary disease (COPD). Proportional odds models identified factors associated with the SPPB, and a principal component analysis (PCA) evaluated how much SPPB variance was explainable by each of its 3 sub-tests., Results: Of 729 enrolled participants, 717 (60% male, mean age 67 years) had full SPPB data. Overall, 76% of patients had some evidence of functional limitations (SPPB total score < 12). Scores < 4 were observed in 71%, 31%, and 22% of participants for the 5STS, 4mGS, and balance sub-tests, respectively. A longer 6-minute walk test and greater quadriceps maximal voluntary contraction decreased the odds of being in a lower score category for SPPB total score and for all 3 sub-tests. Aging, self-reported hypertension and higher dyspnea increased the odds, and being married decreased the odds of being in a lower category for total score. All sub-tests contributed equally to total score., Conclusion: Each of the 3 sub-tests contributed independent information to the SPPB, demonstrating their usefulness for assessing COPD when considered together rather than individually. The 5STS sub-test had the greatest variation in scores and may thus have the best discriminatory power for clinical COPD studies of lower limb performance where only one SPPB test is feasible., Competing Interests: VSB, DM, NG, MA and RT-S are employees of (or were during the time of this study) and hold stock in GlaxoSmithKline. MIP has received payment to his institution or himself for advice on skeletal muscle weakness in COPD from GlaxoSmithKline, Novartis, AstraZeneca, Pfizer, Lilly and Astellas. CEB reports grants from GlaxoSmithKline and Pfizer; consultancy fees from Boehringer Ingelheim and honorarium from Chiesi in the past 3 years. JRC reports grants from Technology Strategy Board/Medical Research Council, during the conduct of the study; personal fees from GlaxoSmithKline, outside the submitted work. WM received research support from GlaxoSmithKline and Pfizer, and was on advisory committees of Almirall, GlaxoSmithKline, Novartis and Pfizer; he was a speaker for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen and Novartis. IBW reports grants from Technology Strategy Board and GlaxoSmithKline during the conduct of the study, and grants from GlaxoSmithKline outside the submitted work., (JCOPDF © 2020.)

The Estonian Biobank, governed by the Institute of Genomics at the University of Tartu (Biobank), has stored genetic material/DNA and continuously collected data since 2002 on a total of 52,274 individuals representing ~5% of the Estonian adult population and is increasing. To explore the utility of data available in the Biobank, we conducted a phenome-wide association study (PheWAS) in two areas of interest to healthcare researchers; asthma and liver disease. We used 11 asthma and 13 liver disease-associated single nucleotide polymorphisms (SNPs), identified from published genome-wide association studies, to test our ability to detect established associations. We confirmed 2 asthma and 5 liver disease associated variants at nominal significance and directionally consistent with published results. We found 2 associations that were opposite to what was published before (rs4374383:AA increases risk of NASH/NAFLD, rs11597086 increases ALT level). Three SNP-diagnosis pairs passed the phenome-wide significance threshold: rs9273349 and E06 (thyroiditis, p = 5.50x10-8); rs9273349 and E10 (type-1 diabetes, p = 2.60x10-7); and rs2281135 and K76 (non-alcoholic liver diseases, including NAFLD, p = 4.10x10-7). We have validated our approach and confirmed the quality of the data for these conditions. Importantly, we demonstrate that the extensive amount of genetic and medical information from the Estonian Biobank can be successfully utilized for scientific research., Competing Interests: AstraZeneca provided support in the form of salaries for author GJ. STACC and Quretec: These funders provided support in the form of salaries for authors SR and JV. GlaxoSmithKline provided support in the form of salaries for authors NG, DW and MA. Pfizer provided support in the form of salaries for author AKL. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Allele-specific analyses to understand frequency differences across populations, particularly populations not well studied, are important to help identify variants that may have a functional effect on disease mechanisms and phenotypic predisposition, facilitating new Genome-Wide Association Studies (GWAS). We aimed to compare the allele frequency of 11 asthma-associated and 16 liver disease-associated single nucleotide polymorphisms (SNPs) between the Estonian, HapMap and 1000 genome project populations. When comparing EGCUT with HapMap populations, the largest difference in allele frequencies was observed with the Maasai population in Kinyawa, Kenya, with 12 SNP variants reporting statistical significance. Similarly, when comparing EGCUT with 1000 genomes project populations, the largest difference in allele frequencies was observed with pooled African populations with 22 SNP variants reporting statistical significance. For 11 asthma-associated and 16 liver disease-associated SNPs, Estonians are genetically similar to other European populations but significantly different from African populations. Understanding differences in genetic architecture between ethnic populations is important to facilitate new GWAS targeted at underserved ethnic groups to enable novel genetic findings to aid the development of new therapies to reduce morbidity and mortality., (© 2019 John Wiley & Sons Ltd.)

Liver enzyme concentrations are measured as safety end points in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT and AST) in subjects randomized to placebo who completed assessments over 36 mo in a cardiovascular outcome trial [the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy ("STABILITY") trial; n = 4,264; mean age: 64.2 yr] or over 12 mo in three trials that enrolled only subjects with type 2 diabetes (T2D) [the DIA trials; n = 308; mean age: 62.4 yr] to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D, and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables and BMI, baseline T2D status, hemoglobin A 1c levels, and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were men, <65 yr old, and obese and who had glomerular filtration rate (GFR) >60 ml·min -1 ·1.73 m -2 . ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA 1c . GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR, and HbA 1c on ALT and AST concentrations and confirm the effect of sex, age, T2D, BMI, and BMI change in subjects receiving placebo in clinical trials. NEW & NOTEWORTHY Clinical trials provide high-quality data on liver enzyme concentrations from subjects randomized to placebo that can be used to investigate the epidemiology of these biomarkers. The adjusted models show the influence of sex, age, time, renal function, type 2 diabetes, HbA 1c , and body mass index on alanine aminotransferase and aspartate aminotransferase concentrations and their relative importance. These factors need to be considered when assessing potential signals of hepatotoxicity in trials of new drugs and in clinical trials investigating subjects with nonalcoholic fatty liver disease.

Background/objectives: Muscle mass decreases with age, and heart failure (HF) patients may experience greater reductions due to pathophysiological processes associated with this disease. Reduced muscle mass may predispose HF patients to functional limitations and increased morbidity and mortality. This study estimated the associations between HF, low muscle mass (LMM), functional limitations and hospitalisation, as well as the combined effect of HF and LMM on these outcomes in a nationally representative sample., Design: A cross-sectional survey., Setting: the National Health and Nutrition Examination Survey 1999-2004., Subjects: A total of 402 HF (weighted 3,994,205) and 7,061 non-HF participants (weighted 91,058,850), ≥45 years with dual-energy X-ray absorptiometry measurements., Methods: the 20th percentile of the sex-specific distribution of lean appendicular mass residuals from linear regression with height and fat mass as predictors, served as the LMM cut-point. Logistic regression provided adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association of HF and LMM with functional limitations and hospitalisation., Results: There were statistically significant adjusted associations between HF and limitations in household chores, walking one-fourth of a mile and hospitalisation (OR (95% CI): 2.5 (1.7 -3.8), 1.9 (1.2 -3.0) and 1.6 (1.1 -2.4), respectively). LMM was significantly associated with limitations in household chores and walking one-fourth of a mile (OR (95% CI): 1.5 (1.2, 1.9) and 1.4 (1.2, 1.7), respectively). Interaction between HF and LMM was noted for the associations with functional limitations., Conclusions: This hypothesis-generating study found a synergistic interaction between HF and LMM; the presence of LMM increased the negative effects of HF. HF patients may experience increased disease burden due to LMM., (© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Used to detect liver disease and injury, baseline liver chemistry distributions were evaluated by age and gender in children without known liver disease. Baseline liver chemistries [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL)] were analyzed from 24 randomized controlled pediatric clinical trials. Using quantile regression, liver chemistry distributions were examined by age and gender; upper limit normal (ULN) ranges were compared to the 97.5th percentiles of the distributions for the specified ages and genders. 5410 subjects without known liver disease (0-18 years; 60% male) were studied. The median ALT varied little with age. In males age 5-18, the ALT 97.5th percentile increased from 34 to 63 IU/L. In both genders, the median and 97.5th percentile AST decreased with age. After age 9, ALP decreased. TBIL increased with age. Despite most liver chemistry 97.5th percentiles changing substantively with age and gender, the reference lab ULN generally changed minimally and did not correlate with the 97.5th percentile. Gender and age specific 97.5th percentile data should therefore be considered for the reference laboratory ULN in children to more accurately detect liver injury and disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The worldwide emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis threatens to make this disease incurable. Drug resistance mechanisms are only partially understood, and whether the current understanding of the genetic basis of drug resistance in M. tuberculosis is sufficiently comprehensive remains unclear. Here we sequenced and analyzed 161 isolates with a range of drug resistance profiles, discovering 72 new genes, 28 intergenic regions (IGRs), 11 nonsynonymous SNPs and 10 IGR SNPs with strong, consistent associations with drug resistance. On the basis of our examination of the dN/dS ratios of nonsynonymous to synonymous SNPs among the isolates, we suggest that the drug resistance-associated genes identified here likely contain essentially all the nonsynonymous SNPs that have arisen as a result of drug pressure in these isolates and should thus represent a near-complete set of drug resistance-associated genes for these isolates and antibiotics. Our work indicates that the genetic basis of drug resistance is more complex than previously anticipated and provides a strong foundation for elucidating unknown drug resistance mechanisms.

Heterogeneity is observed in the patterns of cognition in Alzheimer's disease (AD). Such heterogeneity might suggest the involvement of different etiological pathways or different host responses to pathology. A total of 627 subjects with mild/moderate AD underwent cognitive assessment with the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale-2 (DRS-2). Latent class analysis (LCA) was performed on cognition subscale data to identify and characterize cognitive subgroups. Clinical, demographic, and genetic factors were explored for association with class membership. LCA suggested the existence of four subgroups; one group with mild and another with severe global impairment across the cognitive domains, one group with primary impairments in attention and construction, and another group with primary deficits in memory and orientation. Education, disease duration, age, Apolipoprotein E-epsilon4 (APOE epsilon4) status, gender, presence of grasp reflex, white matter changes, and early or prominent visuospatial impairment were all associated with class membership. Our results support the existence of heterogeneity in patterns of cognitive impairment in AD. Our observation of classes characterized by predominant deficits in attention/construction and memory respectively deserves further exploration as does the association between membership in the attention/construction class and APOE epsilon4 negative status.

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and an increased risk of fracture. Bone mineral density (BMD) is a highly heritable trait and a key determinant of osteoporotic fracture risk, but the genes responsible are incompletely defined. Here, we identified quantitative trait loci (QTL) for regulation of BMD by a genome wide scan involving 3691 individuals from 715 families, who were selected because of reduced BMD values at the lumbar spine (LS-BMD) or femoral neck (FN-BMD) in probands. Linkage analysis was conducted in the study group as a whole with correction for age, gender, weight and height. Further analyses were conducted for men and women separately to identify gender-specific QTL and for those under and over the age of 50 years to distinguish QTL for peak bone mass from those that influence bone mass in older people. No regions of suggestive or significant linkage were identified when data from all subjects were analyzed together. On subgroup analysis, however, we identified a significant QTL for FN-BMD on chromosome 10q21 (LOD score +4.42; men < or =50 years) and two suggestive QTL for LS-BMD on chromosomes 18p11 (LOD score +2.83; women >50 years) and 20q13 (LOD score +3.20; women < or =50 years). We identified five other QTL for BMD with LOD scores of greater than +2.20 on chromosomes 3q25, 4q25, 7p14, 16p13 and 16q23. This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci.