Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data.

Autism spectrum disorder (ASD) is a heterogenous multifactorial neurodevelopmental condition with a significant genetic susceptibility component. Thus, identifying genetic variations associated with ASD is a complex task. Whole-exome sequencing (WES) is an effective approach for detecting extremely rare protein-coding single-nucleotide variants (SNVs) and short insertions/deletions (INDELs). However, interpreting these variants' functional and clinical consequences requires integrating multifaceted genomic information. We compared the concordance and effectiveness of three bioinformatics tools in detecting ASD candidate variants (SNVs and short INDELs) from WES data of 220 ASD family trios registered in the National Autism Database of Israel. We studied only rare (< 1% population frequency) proband-specific variants. According to the American College of Medical Genetics (ACMG) guidelines, the pathogenicity of variants was evaluated by the InterVar and TAPES tools. In addition, likely gene-disrupting (LGD) variants were detected based on an in-house bioinformatics tool, Psi-Variant, that integrates results from seven in-silico prediction tools. Overall, 372 variants in 311 genes distributed in 168 probands were detected by these tools. The overlap between the tools was 64.1, 22.9, and 23.1% for InterVar-TAPES, InterVar-Psi-Variant, and TAPES-Psi-Variant, respectively. The intersection between InterVar and Psi-Variant (I âˆ© P) was the most effective approach in detecting variants in known ASD genes (PPV = 0.274; OR = 7.09, 95% CI = 3.92-12.22), while the union of InterVar and Psi Variant (I U P) achieved the highest diagnostic yield (20.5%).Our results suggest that integrating different variant interpretation approaches in detecting ASD candidate variants from WES data is superior to each approach alone. The inclusion of additional criteria could further improve the detection of ASD candidate variants.

Contribution of modifiable risk factors on the burden of diabetes among women in reproductive age-group in India: a population based cross-sectional study.

The diabetes burden is rapidly accelerating in India, particularly since the 2000s. We explore the burden and contribution of modifiable risk factors in diabetes among reproductive women across geographic regions of India. The study uses data from the National Family Health Survey in India 2015-2016, Census of India 2011, and World Population Prospects 2015. We computed Population Attributable Fractions and the number of total and estimated avoidable diabetic cases across regions. The prevalence of diabetic cases in India were 24.4 per 1000 women, varying across geographic regions. Diabetes affected around 8.2 million women (15-49 years) in India. Overweight (PAF = 19.5%) and obesity (PAF = 18.3%) contributed to the diabetes burden; if mitigated optimally, these can reduce diabetic cases by 2.8 million in India. Controlling diabetes should be region specific for maximum impact. Extending chronic disease screening during maternal and child health consultations might help decelerate the growing menace of diabetes in the country.

Population and sub-national (district) level diversity in missed and dropout of different doses of hepatitis-B vaccine among Indian children aged 12-59 months.

Initiating with a birth dose and a full immunization against hepatitis-B is crucial during early childhood in a country like India where maternal screening of hepatitis-B surface antigen is almost negligible and there is a considerable risk of vertical transmission among children. It is also evident that coverage of hepatitis-B is lowest among all other vaccine doses included in the universal immunization program. In addition, the major challenge is posed by the missed and drop-out of different doses of hepatitis-B among Indian children. In this context, this study examined the population and sub-national level diversity in missed and dropout of different doses of hepatitis-B vaccine in India. We analysed a large dataset of 196,654 children aged 12-59 months from a nationally representative cross-sectional survey, the National Family Health Survey (NFHS), 2015-16. Bivariate cross tabulation was used to estimate the prevalence and the dropout rates. Multivariable-adjusted logistic regression was applied to assess the likelihood of the study events. Within a Bayesian framework, a district-level spatial analysis was conducted employing the Besag-York-Mollie (BYM) Model and the Leroux Model. During 2016, 38% of the children missed the birth dose nationally and 45% of the children did not complete full immunization of hepatitis-B. Findings suggest, presence of socio-economic and demographic gradients in missed and drop-out of different doses of hepatitis-B at national level. The sub-national level spatial analysis identifies more than 280 (out of 640) districts with substantially higher risk (Posterior Median Risk>1) in terms of missed and drop-out of different doses. Most of these districts are scattered across the North-Eastern and Northern part of India. The findings hint the existence of a population and sub-national level diversity in India's missed out and dropout of hepatitis-B doses. Identifying high risk population sub-groups and the districts with children at higher risk of missing the birth and consecutive doses informs the existing knowledge base and helps in formulating community-oriented policies and programs.

Diagnostic Yield and Economic Implications of Whole-Exome Sequencing for ASD Diagnosis in Israel.

Whole-exome sequencing (WES) is an effective approach to identify the susceptibility of genetic variants of autism spectrum disorder (ASD). The Israel Ministry of Health supports WES as an adjunct tool for ASD diagnosis, despite its unclear diagnostic yield and cost effectiveness. To address this knowledge gap, we applied WES to a population-based sample of 182 Bedouin and Jewish children with ASD from southern Israel, and assessed its yield in a gene panel of 205 genes robustly associated with ASD. We then compared the incremental cost-effectiveness ratios (ICERs) for an ASD diagnosis by WES, chromosomal microarray analysis (CMA), and CMA + WES. Overall, 32 ASD candidate variants were detected in 28 children, corresponding to an overall WES diagnostic yield of 15.4%. Interestingly, the diagnostic yield was significantly higher for the Bedouin children than for the Jewish children, i.e., 27.6% vs. 11.1% (p = 0.036). The most cost-effective means for genetic testing was the CMA alone, followed closely by the CMA + WES strategy (ICER = USD 117 and USD 124.8 per child). Yet, WES alone could become more cost effective than the other two approaches if there was to be a 25% increase in its yield or a 50% decrease in its cost. These findings suggest that WES should be recommended to facilitate ASD diagnosis in Israel, especially for highly consanguineous populations, such as the Bedouin.

Linkages between occupation and elevated blood pressure among men in India: a cross-sectional study.

OBJECTIVES: The study aims to examine the linkages between occupation and elevated blood pressure among men aged 25-54 years in India. METHODS: The study is based on the National Family Health Survey India, 2015-16. Age-standardized prevalence rates, χ2 tests and multivariable ordered logistic regression models were used to fulfill the study objectives. RESULTS: In India, more than five out of hundred men of age group 25-54 years are suffering from moderately or severely elevated blood pressure levels. The findings depict an occupation wise inequality in the elevated blood pressure levels. Men belonging to professional-managerial-technical (PR = 6.42 per 100 men) and sales (PR = 6.10 per 100 men) occupational groups are facing a much higher burden. From the fitted multivariable ordered logistic models, we found that highly educated-unemployed and married-unemployed men were found to be at higher risk of elevated blood pressure levels. CONCLUSIONS: The study found linkages between the occupation of men and elevated blood pressure levels in India. Urgent attention is needed to the vulnerable occupational groups like professional-technical-managerial, clerical, and sales with a special focus to the unemployed cohort of the country.

A cross-sectional study on selected child health outcomes in India: Quantifying the spatial variations and identification of the parental risk factors.

This study examined association between selected child health indicators- anaemia, stunting and no/incomplete immunization by inter-linking maternal characteristics at district level and parental characteristics at individual level. A spatial analysis and a binary logit model estimation were employed to draw inferences using the data from the fourth round of National Family Health Survey, 2015-16 of India. Significant spatial clustering of the selected child health outcomes was observed in the country. Mother's educational attainment explained significant district level differential in the selected child health outcomes. At the individual level, parents who are very young, not-educated, socially excluded, belong to poor class were found to be significantly associated with the poor child health outcomes. This study indicates that parental characteristics, such as age, educational attainment and employment substantially determine child health in India, suggesting that an intervention by targeting the households where children are vulnerable is important to improve child health in the country.

Hepatitis B vaccination coverage across India: exploring the spatial heterogeneity and contextual determinants.

BACKGROUND: Although hepatitis B vaccinations have been integrated in the Universal Immunization Program (UIP) in India over a decade, only half of the children are immunized against hepatitis B. The national average in hepatitis B vaccination conceals large variations across states, districts and socio-economic groups. In this context, the aim of this paper is to examine the spatial heterogeneity and contextual determinants of hepatitis B vaccination across the districts of India. METHODS: Using data of 199,899 children aged 12-59 months from the National Family Health Survey-4 (NFHS-4), 2015-16 we have examined the district level spatial distribution and clustering of hepatitis B vaccination with the help of Moran's I and Local Indicator of Spatial Autocorrelation (LISA) measures. We investigated the low coverage of HBV vaccination using spatial autoregressive models (SAR) at the meso scale. And we applied multivariate binary logistic regression analysis to understand the micro-level predictors of hepatitis B vaccination. RESULTS: In 2015-16, 45% of the children aged 12-59 months were not vaccinated against hepatitis B in India. The coverage of hepatitis B vaccine across the districts of India showed a highly significant spatial dependence (Moran's I = 0.580). Bivariate Moran's I confirmed the spatial clustering of hepatitis B vaccination with mother's education, full antenatal care (ANC) utilization, post natal care (PNC) utilization, institutional births and registration of births at the district level. Districts with a very low coverage of HBV vaccine are clustered in the western, north-eastern regions and in some parts of central India. At the unit (child) level, children's hepatitis B immunization status is mostly determined by the socio-economic and demographic characteristics like their mother's educational status, caste, religion, household's wealth condition, birth order, year of birth and the region they belong to. CONCLUSIONS: District level variation in hepatitis B vaccination is spatially heterogeneous and clustered in India with a strong neighbourhood effect. Uptake of hepatitis B vaccine among Indian children is predominantly dependent upon their socio-economic and demographic characteristics.

Exploring the spatial heterogeneity in different doses of vaccination coverage in India.

BACKGROUND: Despite the universalization of immunization against the six vaccine-preventable diseases (VPDs), the coverage of full immunization among the children under age five has remained a challenge globally. The 2015-16 National Family Health Survey (NFHS) indicated large disparity in the coverage of different vaccination doses (BCG, Polio, DPT and Measles) including full immunization across the districts of India. The spatial distribution of poor performing districts in terms of vaccination and the district level spatial, contextual determinants contributing to the low coverage have been poorly studied. Using the recent household survey (NFHS, 2015-16), this study examined the spatial heterogeneity and the factors associated with low vaccination coverage among the children aged 12-23 months across India. DATA AND METHODS: This study used the data from fourth round of National Family Health Survey conducted in 2015-16. District-level prevalence of each of the vaccination doses including full immunization, were analysed. Moran's I, Univariate and Bivariate LISA, Ordinary least square (OLS) and spatial models were employed to achieve the overall aim of the study. RESULTS: At the national level, the prevalence of full immunization was 62 percent. Specific vaccination coverage for BCG, three doses of polio, three doses of DPT and measles were 92, 73, 78 and 81 percent, respectively. The value of the bivariate Moran's I statistics confirmed the spatial dependence between specific vaccination and the set of independent variables. District-level prevalence of the specific vaccine and full immunization showed significant spatial clustering across India. The adjusted coefficients from the spatial error model confirmed that district-level proportion of utilization of post-natal care, institutional births, neonatal tetanus protection of the last birth, women's education and coverage of health insurance showed statistically significant association with every doses of vaccination coverage. CONCLUSION: The full and specific immunization coverage was considerably low in the geographical hotspots as compared to the national coverage. Maternal and child health care services utilization, financial assistance to the mothers through JSY scheme and mother's education were found to determine full immunization as well as the specific vaccination coverage. Appropriate intervention should be designed to reduce the geographical disparity in the coverage of specific and full immunization across India and thus safeguard child health protecting the children from the vaccine preventable diseases across the geography.