Case-control Sample Research Articles

Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes

Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 309 cases and 299 controls, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10−4, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene, in Japanese ASD. The overall results of this case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.

NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches.

Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its brain activity correlates. First, we developed two genetic association analyses using a family-based sample (80 early-onset (EO) trios (offspring onset ≤ 18 years) and 71 adult-onset (AO) trios) and an independent case–control sample (120 healthy subjects (HS), 87 EO and 138 AO patients). Second, we explored the effect of NRN1 on brain activity during a working memory task (N-back task; 39 HS, 39 EO and 39 AO; matched by age, sex and estimated IQ). Different haplotypes encompassing the same three Single Nucleotide Polymorphisms(SNPs, rs3763180–rs10484320–rs4960155) were associated with EO in the two samples (GCT, TCC and GTT). Besides, the GTT haplotype was associated with worse N-back task performance in EO and was linked to an inefficient dorsolateral prefrontal cortex activity in subjects with EO compared to HS. Our results show convergent evidence on the NRN1 association with EO both from genetic and neuroimaging approaches, highlighting the role of neurotrophins in the pathophysiology of SZ.

Characterizing Creative Thinking and Creative Achievements in Relation to Symptoms of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder.

Previous research on ADHD and ASD has mainly focused on the deficits associated with these conditions, but there is also evidence for strengths. Unfortunately, our understanding of potential strengths in neurodevelopmental conditions is limited. One particular strength, creativity, has been associated with both ADHD and ASD. However, the distinct presentations of both conditions beg the question whether ADHD and ASD associate with the same or different aspects of creativity. Therefore, the current study investigated the links between ADHD and ASD symptoms, creative thinking abilities, and creative achievements. To investigate the spectrum of ADHD and ASD symptoms, self-reported ADHD and ASD symptoms, convergent (Remote Associations Test) and divergent thinking (Alternative Uses Task) and creative achievements (Creative Achievement Questionnaire) were assessed in a self-reportedly healthy sample of adults (n = 470). We performed correlation analysis to investigate the relation between ADHD/ASD symptoms and creativity measures. In a second phase of analysis, data from an adult ADHD case-control study (n = 151) were added to investigate the association between ADHD symptoms and divergent thinking in individuals with and without a diagnosis of ADHD.Our analysis revealed that having more ADHD symptoms in the general population was associated with higher scores on all the outcome measures for divergent thinking (fluency, flexibility, and originality), but not for convergent thinking. Individuals with an ADHD diagnosis in the case-control sample also scored higher on measures of divergent thinking. Combining data of the population based and case-control studies showed that ADHD symptoms predict divergent thinking up to a certain level of symptoms. No significant associations were found between the total number of ASD symptoms and any of the creativity measures. However, explorative analyses showed interesting links between the ASD subdomains of problems with imagination and symptoms that relate to social difficulties. Our findings showed a link between ADHD symptoms and divergent thinking abilities that plateaus in the clinical spectrum of symptoms. For ASD symptoms, no relation was found with creativity measures. Increasing the knowledge about positive phenotypes associated with neurodevelopmental conditions and their symptom dimensions might aid psychoeducation, decrease stigmatization and improve quality of life of individuals living with such conditions.

Leveraging unstructured electronic medical record notes to derive population-specific suicide risk models

Electronic medical record (EMR)-based suicide risk prediction methods typically rely on analysis of structured variables such as demographics, visit history, and prescription data. Leveraging unstructured EMR notes may improve predictive accuracy by allowing access to nuanced clinical information. We utilized natural language processing (NLP) to analyze a large EMR note corpus to develop a data-driven suicide risk prediction model. We developed a matched case-control sample of U.S. Department of Veterans Affairs (VA) patients in 2015 and 2016. We randomly matched each case (all patients that died by suicide in that interval, n = 5029) with five controls (patients that remained alive). We processed note corpus using NLP methods and applied machine-learning classification algorithms to output. We calculated area under the curve (AUC) and risk tiers to determine predictive accuracy. NLP-derived models demonstrated strong predictive accuracy. Patients that scored within top 10% of risk model accounted for up to 29% of suicide decedents. NLP-derived model compares positively to other leading prediction methods. Our approach is highly implementable, only requiring access to text data and open-source software. Additional studies should evaluate ensemble models incorporating NLP-derived information alongside more typical structured variables.

Elucidation of the genetic causes of bicuspid aortic valve disease.

The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 × 10-08) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10-16), GATA4 (P = 1.61 × 10-09), and TEX41 (P = 7.68 × 10-04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and ∼20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.

Comparing different versions of computer-aided detection products when reading chest X-rays for tuberculosis.

Computer-aided detection (CAD) was recently recommended by the WHO for TB screening and triage based on several evaluations, but unlike traditional diagnostic tests, software versions are updated frequently and require constant evaluation. Since then, newer versions of two of the evaluated products have already been released. We used a case control sample of 12,890 chest X-rays to compare performance and model the programmatic effect of upgrading to newer versions of CAD4TB and qXR. We compared the area under the receiver operating characteristic curve (AUC), overall, and with data stratified by age, TB history, gender, and patient source. All versions were compared against radiologist readings and WHO's Target Product Profile (TPP) for a TB triage test. Both newer versions significantly outperformed their predecessors in terms of AUC: CAD4TB version 6 (0.823 [0.816-0.830]), version 7 (0.903 [0.897-0.908]) and qXR version 2 (0.872 [0.866-0.878]), version 3 (0.906 [0.901-0.911]). Newer versions met WHO TPP values, older versions did not. All products equalled or surpassed the human radiologist performance with improvements in triage ability in newer versions. Humans and CAD performed worse in older age groups and among those with TB history. New versions of CAD outperform their predecessors. Prior to implementation CAD should be evaluated using local data because underlying neural networks can differ significantly. An independent rapid evaluation centre is necessitated to provide implementers with performance data on new versions of CAD products as they are developed.

The LEGACy study: a European and Latin American consortium to identify risk factors and molecular phenotypes in gastric cancer to improve prevention strategies and personalized clinical decision making globally

BackgroundGastric Cancer (GC) is the fourth most deadly cancer worldwide. Enhanced understanding of its key epidemiological and molecular drivers is urgently needed to lower the incidence and improve outcomes. Furthermore, tumor biology in European (EU) and Latin American (LATAM) countries is understudied. The LEGACy study is a Horizon 2020 funded multi-institutional research approach to 1) detail the epidemiological features including risk factors of GC in current time and 2) develop cost-effective methods to identify and integrate biological biomarkers needed to guide diagnostic and therapeutic approaches with the aim of filling the knowledge gap on GC in these areas.MethodsThis observational study has three parts that are conducted in parallel during 2019–2023 across recruiting centers from four EU and four LATAM countries: Part 1) A case-control study (800 cases and 800 controls) using questionnaires on candidate risk factors for GC, which will be correlated with clinical, demographic and epidemiological parameters. Part 2) A case-control tissue sampling study (400 cases and 400 controls) using proteome, genome, microbiome and immune analyses to characterize advanced (stage III and IV) GC. Patients in this part of the study will be followed over time to observe clinical outcomes. The first half of samples will be used as training cohort to identify the most relevant risk factors and biomarkers, which will be selected to propose cost-effective diagnostic and predictive methods that will be validated with the second half of samples. Part 3) An educational study, as part of our prevention strategy (subjects recruited from the general public) to test and disseminate knowledge on GC risk factors and symptoms by a questionnaire and informative video. Patients could be recruited for more than one of the three LEGACy studies.DiscussionThe LEGACy study aims to generate novel, in-depth knowledge on the tumor biological characteristics through integrating epidemiological, multi-omics and clinical data from GC patients at an EU-LATAM partnership. During the study, cost-effective panels with potential use in clinical decision making will be developed and validated.Trial registrationClinicalTrials.gov Identifiers:Part 1: NCT03957031.Part 2: NCT04015466.Part 3: NCT04019808.

Epigenome-Wide Association Study Identified VTI1A DNA Methylation Associated With Accelerometer-Assessed Physical Activity.

Health benefits of physical activity (PA) may be mediated by DNA methylation alterations. The purpose of the current study was to comprehensively identify CpG sites whose methylation levels were associated with accelerometer-assessed total PA in a general Japanese population. The study participants were from the baseline survey of Saga Japan Multi-institutional Collaborative Cohort. PA was objectively measured by a single-axis accelerometer for 7 d. We used a two-stage strategy. In the discovery stage, we performed a meta-analysis of two epigenome-wide association studies of total PA in 898 individuals (a combination of random sample ( n = 507) and case-control study sample ( n = 391)). Peripheral blood DNA methylation levels were measured using Infinium EPIC or HM450 arrays. In the replication stage, we subsequently examined whether CpG sites significantly associated ( P < 1 × 10 -5 ) with total PA were replicated in another sample ( n = 1711), in which methylation levels were measured by pyrosequencing. A multiple linear regression was performed to determine the cross-sectional association between total PA and methylation levels with adjustment for potential confounders, including body mass index. A fixed-effects model was used in the meta-analysis. Correlations between total PA-associated DNA methylation and several inflammatory markers, such as high-sensitivity C-reactive protein, were also conducted. In the meta-analysis, nine CpG sites were significantly associated with total PA ( P < 1 × 10 -5 ). Among the nine sites, one site cg07030336 (annotated to VTI1A/ZDHHC6 gene) was successfully replicated ( P = 0.009). The current study showed that greater accelerometer-assessed total PA was associated with higher DNA methylation levels at cg07030336 ( VTI1A/ZDHHC6 ) in the general population. In addition, we found a divergent relationship between the methylation levels at cg07030336 and several inflammatory biomarkers.

Performance of Confirmatory Tests for Diagnosing Primary Aldosteronism: a Systematic Review and Meta-Analysis.

Background:Confirmatory tests are recommended for diagnosing primary aldosteronism, but the supporting evidence is unclear.Methods:We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials. Studies evaluating any guideline-recommended confirmatory test (ie, saline infusion test, salt loading test, fludrocortisone suppression test, and captopril challenge test), compared with a reference standard were included. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess the risk of bias. Meta-analyses were conducted using hierarchical summary receiver operating characteristic models.Results:Fifty-five studies were included, comprising 26 studies (3654 participants) for the recumbent saline infusion test, 4 studies (633 participants) for the seated saline infusion test, 2 studies (99 participants) for the salt loading test, 7 studies (386 participants) for the fludrocortisone suppression test, and 25 studies (2585 participants) for the captopril challenge test. Risk of bias was high, affecting more than half of studies, and across all domains. Studies with case-control sampling overestimated accuracy by 7-fold (relative diagnostic odds ratio, 7.26 [95% CI, 2.46–21.43]) and partial verification or use of inconsistent reference standards overestimated accuracy by 5-fold (5.12 [95% CI, 1.48–17.77]). There were large variations in how confirmatory tests were conducted, interpreted, and verified. Under most scenarios, confirmatory testing resulted in an excess of missed cases. The certainty of evidence underlying each test (Grading of Recommendations, Assessment, Development, and Evaluations) was very low.Conclusions:Recommendations for confirmatory testing in patients with abnormal screening tests and high probability features of primary aldosteronism are based on very low-quality evidence and their routine use should be reconsidered.

Estimating risk ratio from any standard epidemiological design by doubling the cases

BackgroundDespite the ease of interpretation and communication of a risk ratio (RR), and several other advantages in specific settings, the odds ratio (OR) is more commonly reported in epidemiological and clinical research. This is due to the familiarity of the logistic regression model for estimating adjusted ORs from data gathered in a cross-sectional, cohort or case-control design. The preservation of the OR (but not RR) in case-control samples has contributed to the perception that it is the only valid measure of relative risk from case-control samples. For cohort or cross-sectional data, a method known as ‘doubling-the-cases’ provides valid estimates of RR and an expression for a robust standard error has been derived, but is not available in statistical software packages.MethodsIn this paper, we first describe the doubling-of-cases approach in the cohort setting and then extend its application to case-control studies by incorporating sampling weights and deriving an expression for a robust standard error. The performance of the estimator is evaluated using simulated data, and its application illustrated in a study of neonatal jaundice. We provide an R package that implements the method for any standard design.ResultsOur work illustrates that the doubling-of-cases approach for estimating an adjusted RR from cross-sectional or cohort data can also yield valid RR estimates from case-control data. The approach is straightforward to apply, involving simple modification of the data followed by logistic regression analysis. The method performed well for case-control data from simulated cohorts with a range of prevalence rates. In the application to neonatal jaundice, the RR estimates were similar to those from relative risk regression, whereas the OR from naive logistic regression overestimated the RR despite the low prevalence of the outcome.ConclusionsBy providing an R package that estimates an adjusted RR from cohort, cross-sectional or case-control studies, we have enabled the method to be easily implemented with familiar software, so that investigators are not limited to reporting an OR and can examine the RR when it is of interest.

Investigating engagement in maladaptive and adaptive exercise behaviors before and during COVID-19.

PurposeEvidence suggests that the coronavirus (COVID-19) pandemic has resulted in increased mental health concerns (e.g., anxiety) and there is ample discussion of how the pandemic has resulted in increases in weight control strategies (e.g., maladaptive exercise behaviors). It remains unclear, however, if maladaptive exercise behaviors are on the rise among non-clinical samples. The objective of this study was to examine college students’ engagement in exercise behaviors (both adaptive and maladaptive) before and during COVID-19.MethodThis study compared reports of compulsive exercise, weight and shape exercise, and positive and healthy exercise in two separate samples recruited from a large southeastern university. Sample 1 was collected pre-COVID-19 (August 2019–February 2020) and Sample 2 was collected during COVID-19 (August 2020–April 2021). Case–control matched samples were generated for this study (N = 144; 52.1% male). Three separate analysis of covariance models tested the differences between (1) adaptive exercise; (2) compulsive exercise; and (3) weight and shape exercise in pre- and during COVID-19 samples, controlling for sex.ResultsIndividuals in the during COVID-19 sample reported significantly more compulsive exercise (p < .001), weight and shape exercise (p < .001), and adaptive exercise (p < .001) compared to individuals in the pre-COVID-19 sample. Effects were of medium to large sizes.ConclusionConsistent with reports from the research literature and popular press, the current study observed that both adaptive and maladaptive exercise were higher among college students during COVID-19 compared to pre-COVID-19.Level of evidence Level V: Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

Patterns of lifestyle behaviours from mid- through later-life in relation to exceptional episodic memory performance in older women: the Nurses' Health Study.

to model and compare patterns from mid- to late-life of body mass index (BMI), alternate Mediterranean diet (A-MeDi) and physical activity, between women with exceptional episodic memory over age 80 and cognitively average controls. Our goal was to examine if lifestyle risk factors in early adulthood may be identified which promote exceptional memory status later in life. a case-control sample nested within the Nurses' Health Study (initiated in 1976), including 7,557 cognitively healthy participants who survived to age 80 and had a cognitive assessment at 80-87years. We defined women with exceptional memory (n = 455) as those with a composite score of episodic memory ≥1.5 standard deviation above the mean. Then, we selected 2,275 cognitively average controls with a score within 1 standard deviation of the mean, matched by age and education. Patterns of BMI, A-MeDi and physical activity at 52-62 through age 82years were estimated between groups using latent process mixed models. In midlife, women with exceptional episodic memory had similar BMI (mean difference [MD] = -0.07kg/m2 [95% confidence intervals {CI}:-0.41; 0.26]) but better adherence to A-MeDi (MD = +0.25 points [0.08; 0.43]) and more physical activity (MD = +3.50 metabolic-equivalent h/week [1.97; 5.09]) than controls. However, with ageing, both groups had similar patterns; both initially gained and later lost weight, had less activity and declining diet quality (all group-by-time interactions P > 0.07). our findings suggest that lifestyle factors differ primarily at earlier ages for those with exceptional versus average episodic memory, thus lifestyle may be most important in earlier life to preserve high levels of memory.

Association between MAP3K4 gene polymorphisms and the risk of schizophrenia susceptibility in a Northeast Chinese Han population.

Schizophrenia stands out as one of the most devastating psychiatric disorders. Previous findings have shown that schizophrenia is a polygenic genetic disorder. Thus, abnormal neurodevelopment and neurogenesis may be associated with the etiology of schizophrenia, so genes which affect these processes may be potential candidate genes of schizophrenia. Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene is a member of the mitogen-activated protein kinase family. Taking into account previous findings, MAP3K4 plays a crucial role in the fundamental pathology of various nervous system diseases. In the present study, we aim to explore the association of MAP3K4 and schizophrenia in an independent case-control sample including 627 schizophrenic patients and 1175 healthy controls from a Northeast Chinese Han population. Both the allelic and genotypic association analyses showed that 6 SNPs in MAP3K4 were significantly associated with schizophrenia (rs590988, rs625977, rs9295134, rs12110787, rs1001808 and rs9355870). After rigorous Bonferroni correction, 4 SNPs (rs9295134, rs12110787, rs1001808 and rs9355870) were still significantly associated with the disease. The haplotype composed of these four SNPs also showed significantly global and individual association with schizophrenia. These results suggest that MAP3K4 is a susceptibility gene for schizophrenia in the Northeast Chinese Han population.

HUBUNGAN ANEMIA DALAM KEHAMILAN DENGAN KEJADIAN PERDARAHAN POSTPARTUM PRIMER di RSUD PUTRI HIJAU MEDAN PERIODE JANUARI 2020-JANUARI 2021

This study aims to determine the relationship between anemia in pregnancy and the incidence of primary postpartum hemorrhage at Putri Hijau Hospital, Medan for the period January 2020 - January 2021. The research method used is an analytic case-control approach. Data were taken from the Register and Patient Medical Records. The population in this study was 447 mothers who gave birth during January 2020 – January 2021. The number of case samples and control samples was made in a 1:1 ratio by following the number of case samples that met the inclusion and exclusion criteria. Bivariate analysis using the Chi Square test found the results: p = 0.000 (p &lt;α, = 0.05), then Ho was rejected, which means that there is a relationship between Anemia in Pregnancy and Primary Postpartum Bleeding Incidence at Putri Hijau Hospital Medan. The strength of the relationship between the two variables is seen based on the contingency coefficient, which is 0.631 which means the strength of the relationship is strong. Then the results of the Odds Ratio (OR) obtained OR = 105 [95% CI 17.8 - 618.7] which means that the range of 17.8 - 618.7 does not exceed the value of 1, so mothers giving birth with anemia in their pregnancy are likely to have primary postpartum hemorrhage. 105 times greater than women who gave birth without anemia in their pregnancy. Based on the results of research and discussion on the relationship between anemia and the incidence of primary postpartum hemorrhage at the Putri Hijau Hospital, Medan for the January 2020 – January 2021 period, it is expected to increase regular health promotion regarding pregnancy and childbirth by involving the role of cadres in providing counseling and involving the role of husband/family in health. pregnant women to minimize the risk of anemia in pregnancy and primary postpartum hemorrhage.

The Case for Case-Cohort: An Applied Epidemiologist's Guide to Reframing Case-Cohort Studies to Improve Usability and Flexibility.

When research questions require the use of precious samples, expensive assays or equipment, or labor-intensive data collection or analysis, nested case-control or case-cohort sampling of observational cohort study participants can often reduce costs. These study designs have similar statistical precision for addressing a singular research question, but case-cohort studies have broader efficiency and superior flexibility. Despite this, case-cohort designs are comparatively underutilized in the epidemiologic literature. Recent advances in statistical methods and software have made analyses of case-cohort data easier to implement, and advances from casual inference, such as inverse probability of sampling weights, have allowed the case-cohort design to be used with a variety of target parameters and populations. To provide an accessible link to this technical literature, we give a conceptual overview of case-cohort study analysis with inverse probability of sampling weights. We show how this general analytic approach can be leveraged to more efficiently study subgroups of interest or disease subtypes or to examine associations independent of case status. A brief discussion of how this framework could be extended to incorporate other related methodologic applications further demonstrates the broad cost-effectiveness and adaptability of case-cohort methods for a variety of modern epidemiologic applications in resource-limited settings.

Whole-exome sequencing in a Japanese multiplex family identifies new susceptibility genes for intracranial aneurysms.

Intracranial aneurysms (IAs) cause subarachnoid hemorrhage, which has high rates of mortality and morbidity when ruptured. Recently, the role of rare variants in the genetic background of complex diseases has been increasingly recognized. The aim of this study was to identify rare variants for susceptibility to IA. Whole-exome sequencing was performed on seven members of a Japanese pedigree with highly aggregated IA. Candidate genes harboring co-segregating rare variants with IA were re-sequenced and tested for association with IA using additional 500 probands and 323 non-IA controls. Functional analysis of rare variants detected in the pedigree was also conducted. We identified two gene variants shared among all four affected participants in the pedigree. One was the splicing donor c.1515+1G>A variant in NPNT (Nephronectin), which was confirmed to cause aberrant splicing by a minigene assay. The other was the missense p.P83T variant in CBY2 (Chibby family member 2). Overexpression of p.P83T CBY2 fused with red fluorescent protein tended to aggregate in the cytoplasm. Although Nephronectin has been previously reported to be involved in endothelial angiogenic functions, CBY2 is a novel molecule in terms of vascular pathophysiology. We confirmed that CBY2 was expressed in cerebrovascular smooth muscle cells in an isoform2-specific manner. Targeted CBY2 re-sequencing in additional case-control samples identified three deleterious rare variants (p.R46H, p.P83T, and p.L183R) in seven probands, showing a significant enrichment in the overall probands (8/501) compared to the controls (0/323) (p = 0.026, Fisher's extract test). NPNT and CBY2 were identified as novel susceptibility genes for IA. The highly heterogeneous and polygenic architecture of IA susceptibility can be uncovered by accumulating extensive analyses that focus on each pedigree with a high incidence of IA.

Asthma-related mortality after release from prison: a retrospective data linkage study

Background People who experience incarceration are at increased risk of asthma and have a higher prevalence of risk factors associated with asthma-related mortality. However, there has been little research on the relationship between asthma and mortality in people released from prison. Objectives This study examined the association between asthma and all-cause and cause-specific mortality, and estimated the increased risk of asthma-related mortality among adults released from prison compared to the age- and sex-matched general population. Design We used data from a nested case-control sample (N = 1658) within a retrospective cohort study of all adults released from prisons in Queensland, Australia, from 1994 to 2007 (N = 42015). Deaths were identified using linkage to national mortality records. Nested study cases were sampled from deaths, with a matched control from the cohort. We examined medical and case management records to identify risk factors potentially associated with mortality. Asthma-related mortality in the cohort was compared to that of the matched general population of Queensland. Results People released from prison were more likely than their age and sex matched general population counterparts to have an asthma-related death (HR = 3.32 95%CI:2.14-5.16). Those who had been identified as having asthma in prison had increased odds of mortality from all-cause (OR = 1.86 95%CI:1.40-2.47), drug-related (OR = 2.5 95%CI:1.40-4.46), cardiovascular-related (OR = 3.2 95%CI:1.57-6.51), and respiratory-related (OR = 3.30 95%CI:1.63-6.70). Conclusion Among people exposed to incarceration, those with asthma are at elevated risk of death after release from custody. Improved management of respiratory disease in this population may contribute to reducing their high rate of preventable mortality.

Genetic Analysis of TB Susceptibility Variants in Ghana Reveals Candidate Protective Loci in SORBS2 and SCL11A1 Genes.

Despite advancements made toward diagnostics, tuberculosis caused by Mycobacterium africanum (Maf) and Mycobacterium tuberculosis sensu stricto (Mtbss) remains a major public health issue. Human host factors are key players in tuberculosis (TB) outcomes and treatment. Research is required to probe the interplay between host and bacterial genomes. Here, we explored the association between selected human/host genomic variants and TB disease in Ghana. Paired host genotype datum and infecting bacterial isolate information were analyzed for associations using a multinomial logistic regression. Mycobacterium tuberculosis complex (MTBC) isolates were obtained from 191 TB patients and genotyped into different phylogenetic lineages by standard methods. Two hundred and thirty-five (235) nondisease participants were used as healthy controls. A selection of 29 SNPs from TB disease-associated genes with high frequency among African populations was assayed using a TaqMan® SNP Genotyping Assay and iPLEX Gold Sequenom Mass Genotyping Array. Using 26 high-quality SNPs across 326 case-control samples in an association analysis, we found a protective variant, rs955263, in the SORBS2 gene against both Maf and Mtb infections (P BH = 0.05; OR = 0.33; 95% CI = 0.32–0.34). A relatively uncommon variant, rs17235409 in the SLC11A1 gene was observed with an even stronger protective effect against Mtb infection (MAF = 0.06; PBH = 0.04; OR = 0.05; 95% CI = 0.04–0.05). These findings suggest SLC11A1 and SORBS2 as a potential protective gene of substantial interest for TB, which is an important pathogen in West Africa, and highlight the need for in-depth host-pathogen studies in West Africa.

Evaluation of genome-wide association signals for nonsyndromic cleft lip with or without cleft palate in a multiethnic Brazilian population

ObjectiveTo evaluate previous nonsyndromic cleft lip with or without cleft palate (NSCL±P) associated signals in 4p16.2, 8p11.23, 12q13.13, 12q13.2 and 17q21.32 in a multiethnic Brazilian cohort. DesignThe single nucleotide polymorphisms (SNPs) rs34246903 in 4p16.2, rs13317 in 8p11.23 (FGFR1, fibroblast growth factor receptor 1), rs3741442 in 12q13.13, rs705704 in 12q13.2 and rs4968247 in 17q21.32 were genotyped with TaqMan allelic discrimination assays in a case-control sample including 801 NSCL±P patients [233 nonsyndromic cleft lip (NSCLO) and 568 nonsyndromic cleft lip and palate (NSCLP)] and 881 healthy controls. Multiple logistic regression analyses, considering sex and genomic ancestry as covariates, were conducted, and the p value was adjusted with Bonferroni multiple correction testing (p ≤ 0.01). ResultsAlthough several associations were identified, those that resisted the multiple correction testing involved the alleles and genotypes of rs34246903 and rs13317. The NSCLO group had a lower frequency of the minor C allele of rs34246903 compared to controls, giving an odds ratio (OR) of 0.74 [95% confidence interval (CI): 0.59–0.93, p = 0.01]. The rs34246903 CC genotype (homozygous) and the recessive model revealed significant protective associations with NSCLO, yielding ORs of 0.50 (95% CI: 0.29–0.85, p = 0.005) and 0.55 (95% CI: 0.33–0.93, p = 0.01) respectively. The presence of C variant allele of rs13317 (OR: 0.81, 95% CI: 0.69–0.96, p = 0.01) as well the TC genotype (OR: 0.77, 95% CI: 0.62–0.94, p = 0.01) and the dominant model (OR: 0.77, 95% CI: 0.63–0.94, p = 0.009) showed significant associations with reduced risk of NSCL±P. ConclusionOur study is the first to support the association of rs34246903 (4p16.2) with NSCLO and rs13317 within FGFR1 with NSCL±P in the highly admixed Brazilian population. Further studies are needed to determine the functionality of those SNPs or to identify the causal markers in linkage disequilibrium with those susceptibility markers.

Longitudinal Temperament Pathways to ADHD Between Childhood and Adolescence.

The current investigation extended prior cross-sectional mapping of etiological factors, transdiagnostic effortful and affective traits, and ADHD symptoms to longitudinal pathways extending from two etiological domains: polygenic and prenatal risk. Hypotheses were (1) genetic risk for ADHD would be related to inattentive ADHD symptoms in adolescence and mediated by childhood effortful control; (2) prenatal smoking would be related to hyperactive-impulsive ADHD symptoms during childhood and mediated by childhood surgency; and (3) there would be age-related variation, such that mediation of genetic risk would be larger for older than younger ages, whereas mediation of prenatal risk would be larger in earlier childhood than at later ages. Participants were 849 children drawn from the Oregon ADHD-1000 Cohort, which used a case control sample and an accelerated longitudinal design to track development from childhood (at year 1 ages 7-13) through adolescence (at year 6 ages 13-19). Results showed the mediational pathway from prenatal smoking through surgency to hyperactivity-impulsivity at Year 1 was significant (indirect effect estimate = .053, p < .01). The mediational pathway from polygenic risk through effortful control to inattention at Year 6 was also significant (indirect effect estimate = .084, p < .01). Both results were independent of the association between inattention and hyperactivity-impulsivity and control for the alternative etiological input and held across parent- and teacher-report of ADHD symptoms. In line with dual pathway models of ADHD, early prenatal risk for hyperactivity-impulsivity appears to operate through surgency, while polygenic genetic risk for inattention appears mediated by effortful control.