Childhood asthma and household exposures to nitrogen dioxide and fine particles: a triple-crossover randomized intervention trial.

OBJECTIVE: Triple-crossover randomized controlled intervention trial to test whether reduced exposure to household NO2 or fine particles results in reduced symptoms among children with persistent asthma. METHODS: Children (n = 126) aged 5-11 years with persistent asthma living in homes with gas stoves and levels of NO2 15 ppb or greater recruited in Connecticut and Massachusetts (2015-2019) participated in an intervention involving three air cleaners configured for: (1) NO2 reduction: sham particle filtration and real NO2 scrubbing; (2) particle filtration: HEPA filter and sham NO2 scrubbing; (3) control: sham particle filtration and sham NO2 scrubbing. Air cleaners were randomly assigned for 5-week treatment periods using a three-arm crossover design. Outcome was number of asthma symptom-days during final 14 days of treatment. Treatment effects were assessed using repeated measures, linear mixed models. RESULTS: Measured NO2 was lower (by 4 ppb, p < .0001) for NO2-reducing compared to control or particle-reducing treatments. NO2-reducing treatment did not reduce asthma morbidity compared to control. In analysis controlling for measured NO2, there were 1.8 (95% CI -0.3 to 3.9, p = .10) fewer symptom days out of 14 in the particle-reducing treatment compared to control. CONCLUSIONS: It remains unknown if using an air cleaner alone can achieve levels of NO2 reduction large enough to observe reductions in asthma symptoms. We observed that in small, urban homes with gas stoves, modest reductions in asthma symptoms occurred using air cleaners that remove fine particles. An intervention targeting exposures to both NO2 and fine particles is complicated and further research is warranted. REGISTRATION NUMBER: NCT02258893.

Analgesic use at ovulation and implantation and human fertility.

BACKGROUND: Studies investigating the effects of pain-relieving medication use on conceiving a pregnancy have shown conflicting results. Furthermore, no previous study has examined medication use around ovulation or implantation and the associations with the probability of conception, fecundability. OBJECTIVE: The objective of the study was to explore the association between fecundability and analgesic use in 3 different menstrual cycle windows (preovulation, periovulation, and implantation) as well as across the entire menstrual cycle. STUDY DESIGN: We analyzed data from a prospective cohort study of women between 30 and 44 years of age who were trying to conceive naturally from 2008 through 2015. Using daily diaries, medication usage was classified as acetaminophen, aspirin, or nonaspirin nonsteroidal antiinflammatory drug during 4 time periods of interest (preovulatory, periovulatory, and implantation) as well as the overall nonmenstrual bleeding days of the cycle. Menstrual cycles during the prospective attempt to become pregnant were enumerated using daily diary menstrual bleeding information. Conception was defined as a positive home pregnancy test. Discrete time fecundability models were used to estimate the fecundability ratio and 95% confidence interval in each of the 4 time windows of interest and for each pain reliever (aspirin use, nonaspirin nonsteroidal antiinflammatory drug use, acetaminophen) compared with no medication use after adjustment for several covariates including age, race, education, body mass index, alcohol and caffeine use, frequency of intercourse, and a history of migraines or uterine fibroids. RESULTS: Medication use was infrequent in the 858 women and 2366 cycles in this analysis. Use of nonaspirin nonsteroidal antiinflammatory drugs or acetaminophen was not associated with fecundability in any of the time windows of interest. Although the sample size was small, aspirin use during the implantation window was associated with increased fecundability (adjusted fecundability ratio [confidence interval]: 2.05 [1.23-3.41]). This association remained when limiting the analysis to cycles with minimal missing data or when adjusting for gravidity. None of the other medications were associated with fecundability. CONCLUSION: Aspirin use around implantation was associated with increased fecundability. These results expand previous literature to suggest the following: (1) implantation may be an important target for the effects of aspirin on conception and (2) aspirin may be beneficial, regardless of pregnancy loss history. These observations should be tested with a clinical trial.

Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data.

Vitamin B12 (hereafter referred to as B12) deficiency in pregnancy is prevalent and has been associated with both lower birth weight (birth weight <2,500 g) and preterm birth (length of gestation <37 weeks). Nevertheless, current evidence is contradictory. We performed a systematic review and a meta-analysis of individual participant data to evaluate the associations of maternal serum or plasma B12 concentrations in pregnancy with offspring birth weight and length of gestation. Twenty-two eligible studies were identified (11,993 observations). Eighteen studies were included in the meta-analysis (11,216 observations). No linear association was observed between maternal B12 levels in pregnancy and birth weight, but B12 deficiency (<148 pmol/L) was associated with a higher risk of low birth weight in newborns (adjusted risk ratio = 1.15, 95% confidence interval (CI): 1.01, 1.31). There was a linear association between maternal levels of B12 and preterm birth (per each 1-standard-deviation increase in B12, adjusted risk ratio = 0.89, 95% CI: 0.82, 0.97). Accordingly, B12 deficiency was associated with a higher risk of preterm birth (adjusted risk ratio = 1.21, 95% CI: 0.99, 1.49). This finding supports the need for randomized controlled trials of vitamin B12 supplementation in pregnancy.

Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: a review and meta-analysis.

Therapy for childhood acute lymphoblastic leukemia (ALL) is associated with 5-year survival rates of ∼90% even after largely eliminating cranial radiation. This meta-analysis assesses the long-term neurocognitive functioning after chemotherapy-only regimens among survivors of childhood ALL. We conducted a systematic review to identify studies that evaluated long-term neurocognitive functioning following treatment of ALL by searching MEDLINE/PubMed, Database of Abstracts of Reviews of Effects, and secondary sources. Studies were included if ALL survivors were in continuous first remission, did not receive any radiation, were at least ≥2 years off therapy or ≥5 years since diagnosis, and were compared with a healthy control group. Weighted mean differences with 95% confidence intervals (CIs) were calculated. Ten nonexperimental studies met all eligibility criteria and included 509 patients and 555 controls. Meta-analysis demonstrated statistically significant moderate impairment across multiple neurocognitive domains evaluated, with intelligence most affected. Significant differences in standard deviation (SD) scores were found for Full Scale intelligence quotient (IQ) (-0.52 SD; 95% CI, -0.68 to -0.37), Verbal IQ (-0.54 SD; 95% CI, -0.69 to -0.40), and Performance IQ (-0.41 SD; 95% CI, -0.56 to -0.27); these SD scores correspond to changes in IQ of 6 to 8 points. Working memory, information processing speed, and fine motor domains were moderately, but statistically significantly, impaired. Meta-analysis of ALL survivors treated without cranial radiation demonstrated significant impairment in IQ and other neurocognitive domains. Patients and their families should be informed about these potential negative effects to encourage surveillance and educational planning. Both preventive and intervention strategies are needed.

Fine Particulates, Preterm Birth, and Membrane Rupture in Rochester, NY.

BACKGROUND: It remains unclear whether fine particulate (PM2.5) exposure affects risk of preterm birth and prelabor rupture of membranes. Unmeasured, poorly measured, and undiscovered individual-level confounders might have introduced bias into past studies that relied on between-women comparisons. METHODS: This was a longitudinal study of preterm birth and prelabor rupture of membranes in Rochester, NY, 2004-2012 (N = 3,264 women, N = 7,121 singleton births). We used conditional logistic regression to match pregnancies to the same woman and estimate the odds of each outcome associated with average PM2.5 concentrations during each trimester and whole pregnancy. RESULTS: For preterm birth, adjusted odds ratios (95% confidence interval) for 1 µg/m increase in PM2.5 in the first trimester, second trimester, third trimester, and whole pregnancy were 1.11 (1.04, 1.18), 1.09 (1.02, 1.16), 1.06 (1.00, 1.13), and 1.17 (1.07, 1.28), respectively. For prelabor rupture of membranes, corresponding odds ratios were 1.00 (0.97, 1.04), 0.99 (0.96, 1.02), 0.99 (0.96, 1.03), and 0.99 (0.94, 1.04), respectively. CONCLUSION: Risk of preterm birth was greater for pregnancies with elevated PM2.5 exposure than other pregnancies to the same women at lower exposure. We did not observe an association between PM2.5 concentrations and prelabor rupture of membranes.

Particulate air pollution, fetal growth and gestational length: The influence of residential mobility in pregnancy.

BACKGROUND: It remains unclear as to whether neglecting residential mobility during pregnancy introduces bias in studies investigating air pollution and adverse perinatal outcomes, as most studies assess exposure based on residence at birth. The aim of this study was to ascertain whether such bias can be observed in a study on the effects of PM10 on risk of preterm birth and fetal growth restriction. METHODS: This was a retrospective study using four pregnancy cohorts of women recruited in Connecticut, USA (N=10,025). We ascertained associations with PM10 exposure calculated using first recorded maternal address, last recorded address, and full address histories. We used a discrete time-to-event model for preterm birth, and logistic regression to investigate associations with small for gestational age (SGA) and term low birth weight (LBW). RESULTS: Pregnant women tended to move to areas with lower levels of PM10. For all outcomes, there was negligible difference between effect sizes corresponding to exposures calculated with first, last and full address histories. For LBW, associations were observed for exposure in second trimester (OR 1.09; 95% CI: 1.04-1.14 per 1µg/m(3) PM10) and whole pregnancy (OR 1.08; 95% CI: 1.02-1.14). For SGA, associations were observed for elevated exposure in second trimester (OR 1.02; 95% CI: 1.00-1.04) and whole pregnancy (OR 1.03; 95% CI: 1.01-1.05). There was insufficient evidence for association with preterm birth. CONCLUSION: PM10 was associated with both SGA and term LBW. However, there was negligible benefit in accounting for residential mobility in pregnancy in this study.

Confronting the missing epistasis problem: on the reproducibility of gene-gene interactions.

Epistasis (gene-gene interaction) is thought to play an integral role in the genetic basis of complex traits, and a significant amount of research has been invested into identifying this phenomenon in human disease. However, the overall success of empirical studies of epistasis in humans is unclear, as such studies are rarely systematically evaluated. Here, we have selected asthma as an example of a well-studied, complex human disease, and provide a critical analysis and replication attempt of nearly all prior reports of epistasis for this disease. Of 191 previously reported interactions, we find that 39.8% were not originally identified using an explicit test for interaction and thus may not have been true epistatic effects to begin with. Moreover, directions of effect were not described for 46.1% of the interactions, which prevents their rigorous replication. In the original studies, attempts at replication were made for 15.2% of the interactions, and 7.3% were actually replicated. In the current study, we were able to evaluate 85.9% of the interactions using a large asthma dataset from the GABRIEL Consortium. None of these interactions could be replicated based on strict criteria. However, we found nominally significant (p < 0.05) evidence in support of 23.8% of the evaluated interactions. Although many reports of epistasis are not robustly supported in the published literature, our results suggest that at least some of these reports may have been true-positive examples of epistasis. In general, improvements in empirical studies of epistasis are called for, in order to better understand the importance of this phenomenon in human disease.

How to increase value and reduce waste when research priorities are set.

The increase in annual global investment in biomedical research--reaching US$240 billion in 2010--has resulted in important health dividends for patients and the public. However, much research does not lead to worthwhile achievements, partly because some studies are done to improve understanding of basic mechanisms that might not have relevance for human health. Additionally, good research ideas often do not yield the anticipated results. As long as the way in which these ideas are prioritised for research is transparent and warranted, these disappointments should not be deemed wasteful; they are simply an inevitable feature of the way science works. However, some sources of waste cannot be justified. In this report, we discuss how avoidable waste can be considered when research priorities are set. We have four recommendations. First, ways to improve the yield from basic research should be investigated. Second, the transparency of processes by which funders prioritise important uncertainties should be increased, making clear how they take account of the needs of potential users of research. Third, investment in additional research should always be preceded by systematic assessment of existing evidence. Fourth, sources of information about research that is in progress should be strengthened and developed and used by researchers. Research funders have primary responsibility for reductions in waste resulting from decisions about what research to do.

The association of indoor tanning and melanoma in adults: systematic review and meta-analysis.

BACKGROUND: Tanning beds are associated with increased risk of melanoma. OBJECTIVE: We sought to update the evidence of the association of melanoma and indoor tanning focusing on frequency of use and exposure to newer tanning beds. METHODS: We searched Scopus, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature on August 14, 2013. We included all observational studies that included patients with melanoma who had indoor tanned. Odds ratios (OR) with 95% confidence intervals (CI) were extracted and combined using generic inverse variance methods assuming a random effects model. RESULTS: In all, 31 studies were included with data available on 14,956 melanoma cases and 233,106 controls. Compared with never using, the OR for melanoma associated with ever using indoor tanning beds was 1.16 (95% CI 1.05-1.28). Similar findings were identified in recent studies with enrollment occurring in the year 2000 onward (OR 1.22, 95% CI 1.03-1.45) and in subjects attending more than 10 tanning sessions (OR 1.34, 95% CI 1.05-1.71). LIMITATIONS: The quality of evidence contributing to review results ranges from poor to mediocre. CONCLUSION: Using tanning beds is associated with a subsequent melanoma diagnosis. Exposure from more than 10 tanning sessions is most strongly associated and there was no statistically significant difference in this association before and after 2000, suggesting that newer tanning technology is not safer than older models.

General, but not abdominal, overweight increases odds of asthma among Norwegian adolescents: the Young-HUNT study.

AIM: The aim of this analysis was to examine the association between asthma and general and abdominal weight status, defined by age- and sex-specific cut-offs for body mass index (BMI) and waist circumference (WC) in adolescents. METHODS: Participants aged 12-19 years in the Young-HUNT (YH) Study (YH1 1995-1997: n = 8222; YH3 2006-2008: n = 7403) completed self-administered questionnaires in school as part of a series of cross-sectional, population-based studies conducted in Nord-Trøndelag, Norway. Weight, height and WC were measured. Adjusted odds ratios (ORs) and 95% Confidence Intervals (CI) for asthma, defined by self-reported physician diagnosis, were calculated. Potential effect modifiers evaluated included sex and pubertal development status (PDS). RESULTS: Asthma was reported by 11.8% of the adolescents in YH1 and 17.0% in YH3. Asthma odds significantly increased for adolescents with general (OR = 1.33; 95%CI: 1.13, 1.56), but not abdominal, overweight and increased for adolescents with general (OR = 1.34; 95%CI: 1.02, 1.75) or abdominal obesity (OR = 1.36; 95%CI: 1.16, 1.60). Underweight had no association with asthma regardless of weight assessment type, and PDS did not meaningfully influence the associations between asthma and weight. CONCLUSION: Overweight and obesity both increased the odds of asthma in 12-19 year-old Norwegians. WC did not add further information to that already provided by BMI to improve our understanding of the association between asthma and weight.

The role of epidemiology in the era of molecular epidemiology and genomics: Summary of the 2013 AJE-sponsored Society of Epidemiologic Research Symposium.

On June 20, 2013, the American Journal of Epidemiology sponsored a symposium at the Society for Epidemiologic Research's 46th Annual Meeting in Boston, Massachusetts, entitled, "What Is the Role of Epidemiology in the Era of Molecular Biology and Genomics?" The future of epidemiology depends on innovation in generating interesting and important testable hypotheses that are relevant to population health. These new strategies will depend on new technology, both in measurement of agents and environment and in the fields of pathophysiology and outcomes, such as cellular epidemiology and molecular pathology. The populations to be studied, sample sizes, and study designs should be selected based on the hypotheses to be tested and include case-control, cohort, and clinical trials. Developing large mega cohorts without attention to specific hypotheses is inefficient, will fail to address many associations with high-quality data, and may well produce spurious results.

New models for large prospective studies: is there a risk of throwing out the baby with the bathwater?

Manolio et al. (Am J Epidemiol. 2012;175:859-866) proposed that large cohort studies adopt novel models using "temporary assessment centers" to enroll up to a million participants to answer research questions about rare diseases and "harmonize" clinical endpoints collected from administrative records. Extreme selection bias, we are told, will not harm internal validity, and "process expertise to maximize efficiency of high-throughput operations is as important as scientific rigor" (p. 861). In this article, we describe serious deficiencies in this model as applied to the United States. Key points include: 1) the need for more, not less, specification of disease endpoints; 2) the limited utility of data collected from existing administrative and clinical databases; and 3) the value of university-based centers in providing scientific expertise and achieving high recruitment and retention rates through community and healthcare provider engagement. Careful definition of sampling frames and high response rates are crucial to avoid bias and ensure inclusion of important subpopulations, especially the medically underserved. Prospective hypotheses are essential to refine study design, determine sample size, develop pertinent data collection protocols, and achieve alliances with participants and communities. It is premature to reject the strengths of large national cohort studies in favor of a new model for which evidence of efficiency is insufficient.

Genome-wide association study of pre-eclampsia detects novel maternal single nucleotide polymorphisms and copy-number variants in subsets of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study cohort.

A genome-wide association study was undertaken to identify maternal single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) associated with pre-eclampsia. Case-control analysis was performed on 1070 Afro-Caribbean (n = 21 cases and 1049 controls) and 723 Hispanic (n = 62 cases and 661 controls) mothers and 1257 mothers of European ancestry (n = 50 cases and 1207 controls) from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. European ancestry subjects were genotyped on Illumina Human610-Quad and Afro-Caribbean and Hispanic subjects were genotyped on Illumina Human1M-Duo BeadChip microarrays. Genome-wide SNP data were analyzed using PLINK. CNVs were called using three detection algorithms (GNOSIS, PennCNV, and QuantiSNP), merged using CNVision, and then screened using stringent criteria. SNP and CNV findings were compared to those of the Study of Pregnancy Hypertension in Iowa (SOPHIA), an independent pre-eclampsia case-control dataset of Caucasian mothers (n = 177 cases and 116 controls). A list of top SNPs were identified for each of the HAPO ethnic groups, but none reached Bonferroni-corrected significance. Novel candidate CNVs showing enrichment among pre-eclampsia cases were also identified in each of the three ethnic groups. Several variants were suggestively replicated in SOPHIA. The discovered SNPs and copy-number variable regions present interesting candidate genetic variants for pre-eclampsia that warrant further replication and investigation.

Association between the SERPINE1 (PAI-1) 4G/5G insertion/deletion promoter polymorphism (rs1799889) and pre-eclampsia: a systematic review and meta-analysis.

The SERPINE1 -675 4G/5G promoter region insertion/deletion polymorphism (rs1799889) has been implicated in the pathogenesis of pre-eclampsia (PE), but the genetic association has been inconsistently replicated. To derive a more precise estimate of the association, a systematic review and meta-analysis was conducted. This study conformed to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed (MEDLINE), Scopus and HuGE Literature Finder literature databases were systematically searched for relevant studies. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the allelic comparison (4G versus 5G) and genotypic comparisons following the co-dominant (4G/4G versus 5G/5G and 4G/5G versus 5G/5G), dominant (4G/4G+4G/5G versus 5G/5G) and recessive (4G/4G versus 4G/5G+5G/5G) genetic models. Between-study heterogeneity was quantified by I(2) statistics and publication bias was appraised with funnel plots. Sensitivity analysis was conducted to evaluate the robustness of meta-analysis findings. Meta-analysis of 11 studies involving 1297 PE cases and 1791 controls found a significant association between the SERPINE1 -675 4G/5G polymorphism and PE for the recessive genetic model (OR = 1.36, 95% CI: 1.13-1.64, P = 0.001), a robust finding according to sensitivity analysis. A low level of between-study heterogeneity was detected (I(2) = 20%) in this comparison, which may be explained by ethnic differences. Funnel plot inspection did not reveal evidence of publication bias. In conclusion, this study provides a comprehensive examination of the available literature on the association between SERPINE1 -675 4G/5G and PE. Meta-analysis results support this polymorphism as a likely susceptibility variant for PE.

Implementing provider-based sampling for the National Children's Study: opportunities and challenges.

BACKGROUND: The National Children's Study (NCS) was established as a national probability sample of births to prospectively study children's health starting from in utero to age 21. The primary sampling unit was 105 study locations (typically a county). The secondary sampling unit was the geographic unit (segment), but this was subsequently perceived to be an inefficient strategy. METHODS AND RESULTS: This paper proposes that second-stage sampling using prenatal care providers is an efficient and cost-effective method for deriving a national probability sample of births in the US. It offers a rationale for provider-based sampling and discusses a number of strategies for assembling a sampling frame of providers. Also presented are special challenges to provider-based sampling pregnancies, including optimising key sample parameters, retaining geographic diversity, determining the types of providers to include in the sample frame, recruiting women who do not receive prenatal care, and using community engagement to enrol women. There will also be substantial operational challenges to sampling provider groups. CONCLUSION: We argue that probability sampling is mandatory to capture the full variation in exposure and outcomes expected in a national cohort study, to provide valid and generalisable risk estimates, and to accurately estimate policy (such as screening) benefits from associations reported in the NCS.

Childhood body mass index and subsequent physician-diagnosed asthma: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Childhood asthma and obesity prevalence have increased in recent years suggesting a potential association. However, the direction of any association is poorly understood and the potential causal-relationship is unknown. METHODS: We examined the association between overweight/obesity, defined by body mass index (BMI) <18 years of age, and subsequent physician-diagnosed incident asthma at least one year after BMI assessment. We sought to explore potential effect modification by sex. PubMed and Embase were searched using keywords and restricted to subjects aged 0-18 years. There were no date or language restrictions. From each study we extracted: authors, publication date, location, overweight/obesity definitions, asthma definitions, number of participants, recruitment duration, description of cohort, follow-up time, adjusted effect estimates (with 95% CI) and estimates of subgroup analysis. RESULTS: Six prospective cohort studies which focused on children <18 years of age met criteria for inclusion. The combined risk ratio (RR) of overweight was associated with asthma (RR = 1.35; 95% CI = 1.15, 1.58). In boys, the combined RR of overweight on asthma was significant (RR = 1.41; 95% CI = 1.05, 1.88). For girls, when BMI was defined by Z-score, the combined RR of overweight on asthma was also significant (RR = 1.19; 95% CI = 1.06, 1.34). The combined risk ratio (RR) of obesity was associated with asthma in both boys and girls (RR = 1.50; 95% CI = 1.22, 1.83), in boys only (RR = 1.40; 95% CI = 1.01, 1.93) and in girls only (RR = 1.53; 95% CI = 1.09, 2.14). CONCLUSIONS: Overweight and, especially, obese children are at increased risk of subsequent physician diagnosed asthma in comparison to normal weight children. Except for sex, no studies reported any other potential effect modifiers. The observed sex effects were inconsistent.

Maternal infection in pregnancy and risk of asthma in offspring.

This study estimates the effect of maternal infections during pregnancy on childhood asthma. One-thousand four-hundred and twenty-eight pregnant women were prospectively followed using structured interviews and chart review until their child's 6th year of life. Infections were identified from outpatient and hospital visits. Childhood asthma was defined as physician diagnosis with symptoms at age six. Adjusted odds ratios were calculated from multivariable logistic regression models. Six-hundred and thirty-five women experienced an infection during pregnancy. Among antepartum infections, maternal urinary tract infections were significantly associated with childhood asthma (aOR 1.60, 95 % CI 1.12-2.29). Chorioamnionitis and maternal group beta streptococcus colonization were not significantly associated with an increased risk in childhood asthma. This study found an increased risk of asthma in children of women diagnosed with urinary tract infections during pregnancy, while other maternal infections did not increase the risk.

Association between XRCC1 polymorphism 399 G->A and glioma among Caucasians: a systematic review and meta-analysis.

BACKGROUND: The x-ray cross complementing group 1 gene (XRCC1) is crucial to proper repair of DNA damage such as single-strand DNA breaks. A non-synonymous polymorphism in XRCC1, 399 G → A, has been shown to reduce effectiveness of such DNA repair and has been associated with the risk of certain cancers. The known risk for glioma from high dose ionizing radiation makes associations between this polymorphism and glioma of particular interest. METHODS: A systematic literature review and meta-analysis was conducted to explore the association between XRCC1 399 G → A and glioma. Subgroup analyses by grade, gender, genotyping method, country in which study was conducted, and study size were conducted when data were available and validity of the results were assessed by influence analyses and exploration of potential publication bias. RESULTS: Six studies were eligible for meta-analysis including data on 2,362 Caucasian glioma cases and 3,085 Caucasian controls. Pooled analysis yielded a significant association between the variant of interest and risk of glioma (OR = 1.17, 95% CI: 1.05-1.30) which was found to be disproportionately driven by a single study. Exclusion of this study, in an influence analysis, produced no statistically significant evidence of association with glioma (OR = 1.10, 95% CI: 0.98-1.23), and no evidence of publication bias. CONCLUSIONS: This meta-analysis does not suggest a major role of the XRCC1 399 G → A polymorphism in influencing risk of glioma among Caucasians. Future studies should report data separately for glioma subtypes to permit stratified analyses for Grade III and Grade IV glioma and examine other polymorphisms in this gene.

Whole-exome sequencing of a pedigree segregating asthma.

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.