Building capacity for health equity analysis in the WHO South-East Asia Region.

"Leaving no one behind" is at the heart of the agenda of the Sustainable Development Goals, requiring that health systems be vigilant to how interventions can be accessed equitably by all, including population subgroups that face exclusion. In the World Health Organization (WHO) South-East Asia Region, inequalities can be found across and within countries but there has been a growing commitment to examining and starting to tackle them. Over the past decade in particular, WHO has been developing an armamentarium of tools to enable analysis of health inequalities and action on health equity. Tools include the Health Equity Assessment Toolkit in built-in database and upload database editions, as well as the Innov8 tool for reorientation of national health programmes. Countries across the region have engaged meaningfully in the development and application of these tools, in many cases aligning them with, or including them as part of, ongoing efforts to examine inequities in population subgroups domestically. This paper reflects on these experiences in Bangladesh, India, Indonesia, Nepal, Sri Lanka and Thailand, where efforts have ranged from workshops to programme reorientation; the creation of assemblies and conferences; and collation of evidence through collaborative research, reviews/synthesis and conferences. This promising start must be maintained and expanded, with greater emphasis on building capacity for interpretation and use of evidence on inequalities in policy-making. This may be further enhanced by the use of innovative mixed methodologies and interdisciplinary approaches to refine and contextualize evidence, with a concomitant shift in attention, developing solutions to redress inequities and anchor health reform within communities. There are many lessons to be learnt in this region, as well as mounting political and popular will for change.

Pre-earthquake national patterns of preschool child undernutrition and household food insecurity in Nepal in 2013 and 2014.

BACKGROUND AND OBJECTIVES: Preschool undernutrition remains a burden in Nepal. This paper reports results of surveys in 2013 and 2014, examining patterns of child nutritional status across the country, associations with household food insecurity and antecedent comparative national data for subsequent evaluations of nutritional status following the earthquake in Nepal in 2015. METHODS AND STUDY DESIGN: A multi-stage sample was drawn comprising 21 sites in 75 districts of the country, representing the mountains, hills and Terai zones, providing proportionate to zonal samples of 4286 and 4947 households and 5401 and 5474 preschool children in each year, respectively. Children 6 to 59 months of age were measured for weight and height, expressed as standardized z-scores for height-for-age (HAZ), weight-for-height (WHZ), and stunting and wasting (<-2 z for each). The household food insecurity access scale (HFIAS) was used to measure food security. RESULTS: Between 2013 and 2014, HAZ decreased from a mean (SD) of -1.46 (1.39) to -1.54 (1.33) z-scores, while the prevalence of stunting increased from 35.5% to 37.4% (p<0.05 for both), evident in the mountains and Terai but not hills. In both years, wasting was highest (~22%) in the Terai versus mountains or hills (~8%). More households were classified food secure in 2014 (73%) than 2013 (59%), evident in all zones. CONCLUSIONS: Two midyear surveys in Nepal revealed a stable nutritional situation among preschool children, reflecting a pause in the long-term decline in stunting noted in previous years. The same period saw a slight reduction in wasting and improved household food security.

Household food production is positively associated with dietary diversity and intake of nutrient-dense foods for older preschool children in poorer families: Results from a nationally-representative survey in Nepal.

BACKGROUND: Nutrition-sensitive interventions supporting enhanced household food production have potential to improve child dietary quality. However, heterogeneity in market access may cause systematic differences in program effectiveness depending on household wealth and child age. Identifying these effect modifiers can help development agencies specify and target their interventions. OBJECTIVE: This study investigates mediating effects of household wealth and child age on links between farm production and child diets, as measured by production and intake of nutrient-dense food groups. METHODS: Two rounds (2013 and 2014) of nationally representative survey data (n = 5,978 observations) were used to measure production and children's dietary intake, as well as a household wealth index and control variables, including breastfeeding. Novel steps used include measuring production diversity in terms of both species grown and food groups grown, as well as testing for mediating effects of family wealth and age of child. RESULTS: We find significant associations between child dietary diversity and agricultural diversity in terms of diversity of food groups and of species grown, especially for older children in poorer households, and particularly for fruits and vegetables, dairy and eggs. With each additional food group produced, log-odds of meeting minimum dietary diversity score (≥4) increase by 0.25 (p = 0.01) for children aged 24-59 months. For younger children aged 18-23 months there is a similar effect size but only in the poorest two quintiles of household wealth, and for infants 6-18 months we find no correlation between production and intake in most models. CONCLUSIONS: Child dietary intake is associated with the composition of farm production, most evident among older preschool children and in poorer households. To improve the nutrition of infants, other interventions are needed; and for relatively wealthier households, own farm production may displace market purchases, which could attenuate the impact of household production on child diets.

The Impact of Balanced Counseling on Contraceptive Method Choice and Determinants of Long Acting and Reversible Contraceptive Continuation in Nepal.

Introduction Long-acting reversible contraceptives (LARCs) reduce rates of unintended pregnancies and repeat abortion. Uptake and continuation rates of LARCs are very low in Nepal, despite free provision from most health facilities. We sought to establish the effectiveness of a new approach to LARC promotion in Nepal. Methods We examined change in contraceptive method mix in Nepal using service data resulting from introduction of a balanced counseling (BC) approach to family planning (FP). All staff located at nine randomly selected FP sites were trained and began applying BC in April and May 2014. Women who accepted LARCs from a participating facility were re-contacted at 1, 3, 6 and 12 months. We estimated the LARC continuation rate and assessed determinants of continuation using descriptive analysis, Kaplan-Meier survival curves and univariate and multivariate Cox proportional hazard analysis. Results A total of 5744 women received BC between April and July 2014. 1580 women (27.5 %) took up LARCs, raising its contribution to contraceptive method mix at [organization] to 40 %, significantly higher than the 15 % recorded in 2013. 913 women were followed-up, and the LARC continuation rate at 12 months was 82 %. Women's reported satisfaction with LARC [AHR 0.23; 95 % CI 0.14-0.39, p = 0.000] was the single strongest determinant of LARC continuation after adjusting for all background characteristics. Discussion The findings suggest BC is an effective approach for increasing LARC uptake in Nepal. The rate of LARC continuation and its determinants are important inputs to strategies for improved delivery of FP services.

Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk.

INTRODUCTION: African-American (AA) individuals have a higher risk for late-onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered. METHODS: We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status. RESULTS: Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences. DISCUSSION: Exploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.

IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242). CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans.

IMPORTANCE: Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. OBJECTIVE: To identify genetic loci associated with late-onset Alzheimer disease in African Americans. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. MAIN OUTCOMES AND MEASURES: Presence of Alzheimer disease according to standardized criteria. RESULTS: Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE ϵ4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 × 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 < empirical P < .001). CONCLUSIONS AND RELEVANCE: In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.

Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians.

Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer's disease (AD), we hypothesized that C9ORF72 expansions might contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a proportion of 0.76% in AD cases versus 0 in control subjects (p = 3.3E-03; 1182 cases, 1039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0-23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological re-evaluation of identified C9ORF72 expansion carriers revealed 9 clinical and/or autopsy confirmed AD and 2 FTD final diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.