Background

Quality of healthcare is an important determinant of future progress in global health. However, the distributional aspects of quality of care have received inadequate attention. We assessed whether high quality maternal care is equitably distributed by (1) mapping the quality of maternal care in facilities located in poorer versus wealthier areas of Kenya; and (2) comparing the quality of maternal care available to Kenyans in and not in poverty.

Methods

We assessed three measures of maternal care quality: facility infrastructure and clinical quality of antenatal care and delivery care, using indicators from the 2010 Kenya Service Provision Assessment (SPA), a standardized facility survey with direct observation of maternal care provision. We calculated poverty of the area served by antenatal or delivery care facilities using the Multidimensional Poverty Index. We used regression analyses and non-parametric tests to assess differences in maternal care quality in facilities located in more and less impoverished areas. We estimated effective coverage with a minimum standard of care for the full population and those in poverty.

Results

A total of 564 facilities offering at least one maternal care service were included in this analysis. Quality of maternal care was low, particularly clinical quality of antenatal and delivery care, which averaged 0.52 and 0.58 out of 1 respectively, compared to 0.68 for structural inputs to care. Maternal healthcare quality varied by poverty level: at the facility level, all quality metrics were lowest for the most impoverished areas and increased significantly with greater wealth. Population access to a minimum standard (≥0.75 of 1.00) of quality maternal care was both low and inequitable: only 17% of all women and 8% of impoverished women had access to minimally adequate delivery care.

Conclusion

The quality of maternal care is low in Kenya, and care available to the impoverished is significantly worse than that for the better off. To achieve the national targets of maternal and neonatal mortality reduction, policy initiatives need to tackle low quality of care, starting with high-poverty areas.

Abstract Background Despite the success of genome-wide association studies for asthma, few, if any, definitively causal variants have been identified and there is still a substantial portion of the heritability of the disease yet to be discovered. Some of this “missing heritability” may be accounted for by family-specific coding variants found to be segregating with asthma. Methods To identify family-specific variants segregating with asthma, we recruited one family from a previous study of asthma as reporting multiple asthmatic and non-asthmatic children. We performed whole-exome sequencing on all four children and both parents and identified coding variants segregating with asthma that were not found in other variant databases. Results Ten novel variants were identified that were found in the two affected offspring and affected mother, but absent in the unaffected father and two unaffected offspring. Of these ten, variants in three genes (PDE4DIP, CBLB, and KALRN) were deemed of particular interest based on their functional prediction scores and previously reported function or asthma association. We did not identify any common risk variants segregating with asthma, however, we did observe an increase in the number of novel, nonsynonymous variants in asthma candidate genes in the asthmatic children compared to the non-asthmatic children. Conclusions This is the first report applying exome sequencing to identify asthma susceptibility variants. Despite having sequenced only one family segregating asthma, we have identified several potentially functional variants in interesting asthma candidate genes. This will provide the basis for future work in which more families will be sequenced to identify variants across families that cluster within genes.

Objective

To evaluate the relationship between birth weight (along with a variety of pre and perinatal characteristics) and the risk of paediatric Hodgkin lymphoma (HL) diagnosed at age <20 years.

Method

We linked California statewide birth records from 1978-2009 and cancer diagnosis data from 1988-2011 to conduct a population-based case-control study with 1216 cases and 4485 controls (matched on birth month and year, sex, and race/ethnicity). Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) of paediatric HL overall and by age of diagnosis, controlling for other perinatal factors.

Results

Compared to children with a normal birth weight (2500-3999 g), those who had a high birth weight (≥4000 g) had an increased risk of paediatric HL overall (OR = 1.23, 95% CI: 1.02-1.48) after adjusting for birth order, maternal age at the time of delivery, and paternal age at the time of delivery. The magnitude of association appeared larger for subgroups of children whose age of diagnosis was 0-10 years (OR = 1.56, 95% CI: 1.04-2.24) or 15-19 years (OR = 1.43, 95% CI: 1.11-1.83), while no association was observed in 11-14 year olds. Compared with firstborn children, those who were third or higher in birth order had a reduced risk of paediatric HL overall (OR = 0.80, 95% CI: 0.67-0.95), and this association also varied by age of diagnosis.

Conclusions

In this study with the largest number of paediatric HL cases, high birth weight was associated with an increased disease risk for most but not all ages of diagnosis. The different findings by age of diagnosis regarding both birth weight and birth order underscore the importance to stratify paediatric HL by age at diagnosis in future etiological investigations.

AbstractBackgroundSpecific genetic contributions for preeclampsia (PE) are currently unknown. This genome-wide association study (GWAS) aims to identify maternal single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) involved in the etiology of PE.MethodsA genome-wide scan was performed on 177 PE cases (diagnosed according to National Heart, Lung and Blood Institute guidelines) and 116 normotensive controls. White female study subjects from Iowa were genotyped on Affymetrix SNP 6.0 microarrays. CNV calls made using a combination of four detection algorithms (Birdseye, Canary, PennCNV, and QuantiSNP) were merged using CNVision and screened with stringent prioritization criteria. Due to limited DNA quantities and the deleterious nature of copy-number deletions, it was decided a priori that only deletions would be selected for assay on the entire case-control dataset using quantitative real-time PCR.ResultsThe top four SNP candidates had an allelic or genotypic p-value between 10-5 and 10-6, however, none surpassed the Bonferroni-corrected significance threshold. Three recurrent rare deletions meeting prioritization criteria detected in multiple cases were selected for targeted genotyping. A locus of particular interest was found showing an enrichment of case deletions in 19q13.31 (5/169 cases and 1/114 controls), which encompasses the PSG11 gene contiguous to a highly plastic genomic region. All algorithm calls for these regions were assay confirmed.ConclusionsCNVs may confer risk for PE and represent interesting regions that warrant further investigation. Top SNP candidates identified from the GWAS, although not genome-wide significant, may be useful to inform future studies in PE genetics.

Linking birth records and cancer registry data from California, we conducted a population-based study with 23,419 cases and 87,593 matched controls born during 1978-2009 to investigate the relationship of parental age to risk of pediatric cancer. Compared with children born to mothers aged 20-24 years, those born to mothers in older age groups had a 13%-36% higher risk of pediatric cancer; the odds ratio for each 5-year increase in maternal age was 1.06 (95% confidence interval (CI): 1.04, 1.09). For cancer diagnosed in children in age groups 0-14 years and 15-19 years, the odds ratios for each 5-year increase in maternal age were 1.05 (95% CI: 1.02, 1.07) and 1.14 (95% CI: 1.09, 1.19), respectively. Having an older father also conferred an increased risk, with an odds ratio for each 5-year increase of 1.03 (95% CI: 1.02, 1.05) for cancer diagnosed at ages 0-19 years and 1.03 (95% CI: 1.02, 1.05) for cancer diagnosed at ages 0-14 years. While advancing maternal age increased risk of leukemia and central nervous system tumors, older paternal age was not associated with risk of either type. Both maternal and paternal older ages were associated with risk of lymphoma. In this large, population-based record-linkage study, advancing parental age, especially advancing maternal age, was associated with higher pediatric cancer risk, with variations across types of cancer.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite overlap between genetic risk loci for ALL and hematologic traits, the etiological relevance of dysregulated blood-cell homeostasis remains unclear. We investigated this question in a genome-wide association study (GWAS) of childhood ALL (2,666 affected individuals, 60,272 control individuals) and a multi-trait GWAS of nine blood-cell indices in the UK Biobank. We identified 3,000 blood-cell-trait-associated (p < 5.0 × 10^-8) variants, explaining 4.0% to 23.9% of trait variation and including 115 loci associated with blood-cell ratios (LMR, lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio). ALL susceptibility was genetically correlated with lymphocyte counts (r_g = 0.088, p = 4.0 × 10^-4) and PLR (r_g = -0.072, p = 0.0017). In Mendelian randomization analyses, genetically predicted increase in lymphocyte counts was associated with increased ALL risk (odds ratio [OR] = 1.16, p = 0.031) and strengthened after accounting for other cell types (OR = 1.43, p = 8.8 × 10^-4). We observed positive associations with increasing LMR (OR = 1.22, p = 0.0017) and inverse effects for NLR (OR = 0.67, p = 3.1 × 10^-4) and PLR (OR = 0.80, p = 0.002). Our study shows that a genetically induced shift toward higher lymphocyte counts, overall and in relation to monocytes, neutrophils, and platelets, confers an increased susceptibility to childhood ALL.

The relationship of mode of delivery to risk of childhood acute lymphoblastic leukemia (ALL) is uncertain. After linking birth records and cancer registry data from California, we conducted a population-based case-control study to investigate the role of delivery by cesarean section (C-section) in the etiology of childhood ALL. This study included 5,081 cases and 18,927 matched controls born in 1978-2009; more detailed data were available on type of C-section (i.e., elective vs. emergency) for a subset of 1,552 cases and 5,688 controls. No association was observed between C-section overall and childhood ALL risk (<15 years of age), but elective C-section was associated with a significantly elevated risk of ALL (odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.01, 1.36). At the peak ages of ALL incidence (2-4 years), C-section was associated with an 11% higher risk of ALL (OR = 1.11, 95% CI: 1.01, 1.22) compared with vaginal delivery, and the magnitude of the association was larger for elective C-section (OR = 1.38, 95% CI: 1.11, 1.70). Emergency C-section was not associated with childhood ALL. Because of design features minimizing nonparticipation and inaccurate recall, this record linkage-based study is less prone to bias. Our results suggest that delivery by elective C-section was associated with a higher risk of childhood ALL, especially at the peak ages of incidence. It is important to evaluate possible mechanisms, because this potential risk factor is modifiable.

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different "genetic signatures" of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.

Objectives

Using a novel candidate SNP approach, we aimed to identify a possible genetic basis for the higher glioma incidence in Whites relative to East Asians and African-Americans.

Methods

  We hypothesized that genetic regions containing SNPs with extreme differences in allele frequencies across ethnicities are most likely to harbor susceptibility variants. We used International HapMap Project data to identify 3,961 candidate SNPs with the largest allele frequency differences in Whites compared to East Asians and Africans and tested these SNPs for association with glioma risk in a set of White cases and controls. Top SNPs identified in the discovery dataset were tested for association with glioma in five independent replication datasets.

Results

No SNP achieved statistical significance in either the discovery or replication datasets after accounting for multiple testing or conducting meta-analysis. However, the most strongly associated SNP, rs879471, was found to be in linkage disequilibrium with a previously identified risk SNP, rs6010620, in RTEL1. We estimate rs6010620 to account for a glioma incidence rate ratio of 1.34 for Whites relative to East Asians.

Conclusion

We explored genetic susceptibility to glioma using a novel candidate SNP method which may be applicable to other diseases with appropriate epidemiologic patterns.

Childhood acute lymphoblastic leukemia (ALL) (age 0-14 years) is 20% more common in Latino Americans than non-Latino whites. We conduct a genome-wide association study in a large sample of 3263 Californian children with ALL (including 1949 of Latino heritage) and 3506 controls matched on month and year of birth, sex, and ethnicity, and an additional 12,471 controls from the Kaiser Resource for Genetic Epidemiology Research on Aging Cohort. Replication of the strongest genetic associations is performed in two independent datasets from the Children's Oncology Group and the California Childhood Leukemia Study. Here we identify new risk loci on 17q12 near IKZF3/ZPBP2/GSDMB/ORMDL3, a locus encompassing a transcription factor important for lymphocyte development (IKZF3), and at an 8q24 region known for structural contacts with the MYC oncogene. These new risk loci may impact gene expression via local (four 17q12 genes) or long-range (8q24) interactions, affecting function of well-characterized hematopoietic and growth-regulation pathways.