Sepsis research: Heterogeneity as a foundation rather than an afterthought.

Our understanding of sepsis has been hampered by the implicit assumption that sepsis is a homogeneous disease. In this issue of Cell Genomics, Burnham et al.1 have started to characterize the genetic variants and regulatory networks that underlie variations in the individual response to sepsis; this may eventually enable targeted intervention development.

Spatial availability of federally qualified health centers and disparities in health services utilization in medically underserved areas.

Federally qualified health centers (FQHCs) improve access to care for important health services (e.g., preventive care), particularly among marginalized and underserved communities. However, whether spatial availability of FQHCs influences care-seeking behavior for medically underserved residents is unclear. The objective of this study was to examine the relationships of present-day zip-code level availability of FQHCs, historic redlining, and health services utilization (i.e., at FQHCs and any health clinic/facility) in six large states. We further examined these associations by states, FQHC availability (i.e., 1, 2-4 and ≥5 FQHC sites per zip code) and geographic areas (i.e., urbanized vs. rural, redlined vs. non-redlined sections of urban areas). Using Poisson and multivariate regression models, we found that in medically underserved areas, having at least one FQHC site was associated with greater likelihood of patients seeking health services at FQHCs [rate ratio (RR) = 3.27, 95%CI: 2.27-4.70] than areas with no FQHCs available, varying across states (RRs = 1.12 to 6.33). Relationships were stronger in zip codes with ≥5 FQHC sites, small towns, metropolitan areas, and redlined sections of urban areas (HOLC D-grade vs. C-grade: RR = 1.24, 95%CI: 1.21-1.27). However, these relationships did not remain true for routine care visits at any health clinic or facility (ß = -0.122; p = 0.008) or with worsening HOLC grades (ß = -0.082; p = 0.750), potentially due to the contextual factors associated with FQHC locations. Findings suggest that efforts to expand FQHCs may be most impactful for medically underserved residents living in small towns, metropolitan areas and redlined sections of urban areas. Because FQHCs can provide high quality, culturally competent, cost-effective access to important primary care, behavioral health, and enabling services that uniquely benefit low-income and marginalized patient populations, particularly those who have been historically denied access to health care, improving availability of FQHCs may be an important mechanism for improving health care access and reducing subsequent inequities for these underserved groups.

Food Insecurity and Nutritional Challenges in Adolescent and Young Adult Cancer Survivors in the U.S.A.: A Narrative Review and Call to Action.

Advancements in cancer treatments over the past several decades have led to improved cancer survival in adolescents and young adults (AYAs, ages 15-39 years). However, AYA cancer survivors are at an increased risk for "late effects", including cardiovascular, pulmonary and bone diseases as well as fatigue, infertility and secondary cancers. The treatments for cancer may also alter taste, lead to nutritional deficiencies and increase financial burdens that, when taken together, may increase the risk of food and nutrition security in AYA cancer survivors. Furthermore, although AYAs are often merged together in cancer survivorship studies, adolescents and young adults have distinct developmental, psychosocial and pathophysiological differences that may modify their risk of nutritional challenges. In this narrative review and "Call to Action", rationale is provided for why there is a need to better understand nutritional challenges and food insecurity in AYA cancer survivors as a special population. Then, recommendations for next steps to advance knowledge and policy in this field are provided. In particular, integrating screening for food and nutrition insecurity and enhancing awareness of existing resources (e.g., the Supplemental Nutrition Assistance Program, SNAP) might help AYA cancer survivors combat nutritional deficiencies and reduce late effects while improving their overall survival and quality of life.

Racial and Ethnic Differences in Antiseizure Medications Among People With Epilepsy on Medicaid: A Case of Potential Inequities.

Background and Objectives: Being on a newer, second-, and third-generation antiseizure medication (ASM) may represent an important marker of quality of care for people with epilepsy. We sought to examine whether there were racial/ethnic differences in their use. Methods: Using Medicaid claims data, we identified the type and number of ASMs, as well as the adherence, for people with epilepsy over a 5-year period (2010-2014). We used multilevel logistic regression models to examine the association between newer-generation ASMs and adherence. We then examined whether there were racial/ethnic differences in ASM use in models adjusted for demographics, utilization, year, and comorbidities. Results: Among 78,534 adults with epilepsy, 17,729 were Black, and 9,376 were Hispanic. Overall, 25.6% were on older ASMs, and being solely on second-generation ASMs during the study period was associated with better adherence (adjusted odds ratio: 1.17, 95% confidence interval [CI]: 1.11-1.23). Those who saw a neurologist (3.26, 95% CI: 3.13-3.41) or who were newly diagnosed (1.29, 95% CI: 1.16-1.42) had higher odds of being on newer ASMs. Importantly, Black (0.71, 95% CI: 0.68-0.75), Hispanic (0.93, 95% CI: 0.88-0.99), and Native Hawaiian and Other Pacific Island individuals (0.77, 95% CI: 0.67-0.88) had lower odds of being on newer ASMs when compared with White individuals. Discussion: Generally, racial and ethnic minoritized people with epilepsy have lower odds of being on newer-generation ASMs. Greater adherence by people who were only on newer ASMs, their greater use among people seeing a neurologist, and the opportunity of a new diagnosis point to actionable leverage points for reducing inequities in epilepsy care.

Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway.

BACKGROUND: Late-Onset Neonatal Sepsis (LOS) is a rare condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not completely preventable, identifying susceptibility factors is critical to characterizing the pathophysiology and developing interventions. Prior studies demonstrated both genetics and infant sex influence susceptibility. Our study was designed to identify LOS associated genetic variants. METHODS: We performed an exploratory genome wide association study (GWAS) with 224 LOS cases and 273 controls from six European countries. LOS was defined as sepsis presenting from 3 to 90 days of age; diagnosis was established by clinical criteria consensus guidelines. We tested for association with both autosomal and X-chromosome variants in the total sample and in sex-stratified analyses. RESULTS: In total, 71 SNPs associated with neonatal sepsis at p < 1 × 10-4 in at least one analysis. Most importantly, sex-stratified analyses revealed associations with multiple SNPs (28 in males and 16 in females), but no variants from single-sex analyses associated with sepsis in the other sex. Pathway analyses showed NOTCH signaling is over-represented among genes linked to these SNPS. CONCLUSION: Our results indicate genetic susceptibility to LOS is sexually dimorphic and corroborate that NOTCH signaling plays a role in determining risk. IMPACT: Genes associate with late onset neonatal sepsis. Notch pathway genes are overrepresented in associations with sepsis. Genes associating with sepsis do not overlap between males and females. Sexual dimorphism can lead to sex specific treatment of sepsis.

Hemizygosity can reveal variant pathogenicity on the X-chromosome.

Pathogenic variants on the X-chromosome can have more severe consequences for hemizygous males, while heterozygote females can avoid severe consequences due to diploidy and the capacity for nonrandom expression. Thus, when an allele is more common in females this could indicate that it increases the probability of early death in the male hemizygous state, which can be considered a measure of pathogenicity. Importantly, large-scale genomic data now makes it possible to compare allele proportions between the sexes. To discover pathogenic variants on the X-chromosome, we analyzed exome data from 125,748 ancestrally diverse participants in the Genome Aggregation Database (gnomAD). After filtering out duplicates and extremely rare variants, 44,606 of the original 348,221 remained for analysis. We divided the proportion of variant alleles in females by the proportion in males for all variant sites, and then placed each variant into one of three a priori categories: (1) Reference (Primarily synonymous and intronic), (2) Unlikely-to-be-tolerated (Primarily missense), and (3) Least-likely-to-be-tolerated (Primarily frameshift). To assess the impact of ploidy, we compared the distribution of these ratios between pseudoautosomal and non-pseudoautosomal regions. In the non-pseudoautosomal regions, mean female-to-male ratios were lowest among Reference (2.40), greater for Unlikely-to-be-tolerated (2.77) and highest for Least-likely-to-be-tolerated (3.28) variants. Corresponding ratios were lower in the pseudoautosomal regions (1.52, 1.57, and 1.68, respectively), with the most extreme ratio being just below 11. Because pathogenic effects in the pseudoautosomal regions should not drive ratio increases, this maximum ratio provides an upper bound for baseline noise. In the non-pseudoautosomal regions, 319 variants had a ratio over 11. In sum, we identified a measure with a dataset specific threshold for identifying pathogenicity in non-pseudoautosomal X-chromosome variants: the female-to-male allele proportion ratio.

Improving Surveillance and Epidemic Response in Ohio Childcare Settings.

At the start of the Coronavirus Disease of 2019 (COVID-19) pandemic, the risk of cases in childcare programs was unknown. Thus, a rapid-response research approach was launched in Ohio childcare settings. Passive surveillance data from a state-operated incident reporting system were evaluated to estimate the number of COVID-19 cases from 15 August 2020 to 1 January 2021. Additionally, active surveillance with self-administered reverse transcriptase-polymerase chain reaction (RT-PCR) tests were conducted among staff at 46 childcare programs. Finally, six zoom-based focus groups with program administrators were used to gain feedback. Staff and children in childcare settings contributed 0.38% and 0.15% of the COVID-19 cases in Ohio during this timeframe, respectively. RT-PCR testing identified 3 unrecognized cases (0.88% of tests), and all occurred when the statewide positivity rate was >5%. Focus groups revealed that access to affordable cleaning supplies, masks, and reliable staffing were critical. Perhaps most importantly, we conclude that expanding the incident reporting system to include a childcare census would allow for the tracking of future health problems with highly valuable incidence rate estimations.

Inconsistent Medicaid Coverage is Associated with Negative Health Events for People with Epilepsy.

OBJECTIVE: Examine the association between gaps in Medicaid coverage and negative health events (NHEs) for people with epilepsy (PWE). METHODS: Using five years of Medicaid claims for PWE, we identified gaps in Medicaid coverage. We used logistic regression to evaluate the association between a gap in coverage and being in the top quartile of NHEs and factors associated with having a gap. These models adjusted for: demographics, residence, medication adherence, disease severity, and comorbidities. RESULTS: Of 186,616 PWE, 21.7% had a gap in coverage. The odds of being in the top quartile of NHEs per year were 66% higher among those with a gap (OR: 1.66; 95% CI: 1.61, 1.70). Being female, younger, and having psychiatric comorbidities increased the odds of having a gap. CONCLUSIONS: Gaps in Medicaid coverage are associated with being a high utilizer during covered periods. Specific groups could be targeted with interventions to reduce churning.

Understanding SNAP Recipient Characteristics to Guide Equitable Expansion of Nutrition Incentive Programs in Diverse Food Retail Settings.

Structural barriers, such as food costs, reduce access to healthy foods for populations with limited income, including those benefitting from the Supplemental Nutrition Assistance Program (SNAP). Nutrition incentive programs seek to address this barrier. Evaluations of SNAP-based incentive programming often focus on one setting (i.e., either farmers' markets or grocery stores). We examined use patterns, characteristics, and preferences among 253 SNAP consumers with access to incentive programming at both a farmers' market and a grocery store located within five miles of their home. Cross-sectional survey data were collected in 2019 in two Ohio cities. Despite geographic access, 45% of those surveyed were not using the incentive program; most non-users (80.5%) were unaware of the program. Program users compared to non-users had higher household incomes (p < 0.001) and knew more people using the program (p < 0.001). Grocery stores were the most common setting of use (59%); 29% used at farmers' markets; 11% used in both settings. User characteristics varied by store setting based on demographics, program experience, fruit and vegetable purchasing and consumption patterns, and social dynamics related to use. Our findings support comprehensive awareness-raising efforts and tailored implementation of incentive programming that attends to diverse segments of SNAP consumers to promote equity in program reach.

Health outcomes in redlined versus non-redlined neighborhoods: A systematic review and meta-analysis.

BACKGROUND: Redlining was a racialized zoning practice in the U.S. that blocked fair access to home loans during the 1930s, and recent research is illuminating health problems in the current residents of these historically redlined areas. However, this work has not yet been holistically summarized. Here, we present the first systematic review and meta-analysis comparing health outcomes in redlined versus non-redlined neighborhoods in U.S. cities. METHODS: We extracted relevant articles in PubMed, Web of Science, Cochrane and Science Direct databases published from January 2010 to September 2021. RESULTS: The search revealed 12 studies on preterm births (n = 3), gunshot-related injuries (n = 2), cancer (n = 1), asthma (n = 1), self-rated health (n = 1), multiple health outcomes (n = 2), heat-related outcomes (n = 1) and COVID-19 incidence and mortality (n = 1). A meta-analysis of three studies found the odds of having preterm birth was significantly higher (OR = 1.41, 95% CI: 1.05, 1.88; p = 0.02) among women living in redlined areas compared to those in non-redlined areas. Review of other outcomes revealed that gunshot-related injuries, asthma, heat-related outcomes, and multiple chronic conditions were worse in redlined areas, while associations with cancer varied by cancer type. In terms of cause-specific mortality, one study revealed no link between residential redlining and infant mortality rate, while one study on COVID-19 outcomes was inconclusive. CONCLUSIONS: Overall, this review presents evidence that living in historically redlined areas is associated with increased risk of multiple serious adverse health outcomes. Further research on mechanisms, remediation, and neighborhood-level interventions is needed to strengthen the understanding of the impacts of redlining on health.

Food system dynamics structuring nutrition equity in racialized urban neighborhoods.

BACKGROUND: The food system is a social determinant of health and a leverage point for reducing diet-related racial inequities. Yet, food system interventions have not resulted in sustained improvement in dietary outcomes for underrepresented minorities living in neighborhoods with a history of disinvestment. Research is needed to illuminate the dynamics structuring food systems in racialized neighborhoods to inform intervention development. OBJECTIVES: To conduct participatory research examining the complexity and inequity of food systems in historically redlined neighborhoods to identify feedback mechanisms to leverage in efforts to transform system outcomes for racial equity. METHODS: We conducted a mixed-methods study in Cleveland, Ohio, USA from 2018 to 2021 using participatory system dynamic modeling with 30 academic and community partners, in-depth qualitative interviews with 22 key stakeholders, and public convenings with 250 local food policy council affiliates. Data were synthesized into causal loop diagrams depicting feedback mechanisms reinforcing or balancing neighborhood-level food system dynamics. RESULTS: We identified 10 feedback mechanisms structuring nutrition equity, which was identified as a meta-goal for food systems in racialized neighborhoods. Feedback mechanisms were organized in 3 domains: 1) meeting basic food needs with dignity (i.e., side hustle, government benefits, emergency food assistance, stigma, and stereotypes); 2) local food supply and demand dynamics (i.e., healthy food retail, job security, food culture, and norms); and 3) community empowerment and food sovereignty (i.e., community power, urban agriculture, risk of gentrification). Five exogenous factors moderate feedback dynamics: neighborhood crisis, neighborhood investments, household costs, government benefit funding, and voter participation. CONCLUSIONS: We identified nutrition equity as an overarching goal for local food systems, which reflects a state of having freedom, agency, and dignity in food traditions resulting in people and communities healthy in body, mind, and spirit. It is a transformative goal designed to spur system-level interventions that further racial equity through improved local food system dynamics.

Elevated Dietary Inflammation Among Supplemental Nutrition Assistance Program Recipients Provides Targets for Precision Public Health Intervention.

INTRODUCTION: The Supplemental Nutrition Assistance Program was designed to prevent food insecurity among low-income Americans and has been linked to improvements in pregnancy health, long-term child development, and criminal recidivism. However, the pursuit of food security does not ensure nutritional sufficiency, and the program has not improved diet quality or cardiometabolic mortality (i.e., heart disease, stroke, diabetes). In this study, longitudinal cohort data are used to identify by Supplemental Nutrition Assistance Program status the proinflammatory characteristics that predispose to chronic disease. METHODS: Between 2015 and 2018, annual 24-hour dietary recalls were conducted with 409 residents from low-income, urban neighborhoods in Columbus and Cleveland, Ohio (statistical analysis started in 2019). The Dietary Inflammatory Index was calculated. It provides empirically validated estimates of the internal inflammation that each diet should produce; higher Dietary Inflammatory Index scores have been associated with elevated inflammatory biomarkers. Finally, associations between Supplemental Nutrition Assistance Program and Dietary Inflammatory Index were evaluated, and dietary components that differed by Supplemental Nutrition Assistance Program status were identified. RESULTS: Supplemental Nutrition Assistance Program recipients had higher Dietary Inflammatory Index scores (+0.40, 95% CI=0.09, 0.70) and a consistently lower intake of 4 anti-inflammatory nutrients (dietary fiber, ß-carotene, magnesium, vitamin E) than nonrecipients. Vitamin D intake did not differ by Supplemental Nutrition Assistance Program status but was well below the Recommended Daily Allowance in this sample. CONCLUSIONS: Supplemental Nutrition Assistance Program recipients had elevated Dietary Inflammatory Index scores, implying higher diet-driven inflammation. This was due, in part, to low intake of 4 anti-inflammatory food components, which were higher yet still nutritionally insufficient among nonrecipients. Findings highlight specific nutritional targets for improving public health through dietary change.

Low Omega-3 intake is associated with high rates of depression and preterm birth on the country level.

Low circulating levels of long chain omega-3 polyunsaturated fatty acids (LC omega-3 PUFA) have been linked to major depressive disorder (MDD) and preterm birth (PTB), and prenatal depression associates with PTB. We therefore hypothesized that low Omega-3 intake would associate with higher MDD and PTB rates on the country-level. To test this hypothesis, we obtained country-level estimates for omega-3 intake, MDD prevalence, PTB rate, and per capita income for 184 countries in 2010. We then estimated the LC omega-3 PUFA levels that these intakes produce by accounting for direct consumption and the endogenous conversion of ingested plant-based precursors. Penalized splines indicated that MDD and PTB rates decreased linearly with increasing LC omega-3 PUFA, up to ~ 1000 mg/day for MDD and up to ~ 550 mg/day for PTB. Adjusted linear regression models below these thresholds revealed that a one standard deviation increase in LC omega-3 PUFA (380 mg/day) was associated with an MDD decrease of 5 cases/1000 people and a PTB decrease of 15 cases/1000 livebirths. In light of the extensive prior evidence on the individual-level, these findings indicate that low intake of LC omega-3 PUFA and its precursors may be elevating MDD and PTB rates in 85% of the countries studied.

Omega-3 polyunsaturated fatty acid intake norms and preterm birth rate: a cross-sectional analysis of 184 countries.

BACKGROUND: The preponderance of evidence now indicates that elevated long-chain omega-3 polyunsaturated fatty acid (LC omega-3 PUFA) intake is often associated with reduced risk of preterm birth (PTB). This conclusion is based on recent meta-analyses that include several studies that reported null findings. We probed the reasons for this heterogeneity across studies and its implications for PTB prevention using country-level data. METHODS: We analysed the relationship between national PTB rates (<37 weeks of gestation) and omega-3 PUFA intake norms from 184 countries for the year 2010. To estimate the total LC omega-3 PUFA levels (eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA]) that these norms produce we utilised a metric that accounts for (1) seafood-based omega-3 intake (EPA/DHA) and (2) plant-based omega-3 intake (alpha-linolenic acid [ALA]), ~20% of which is converted to EPA/DHA in vivo. We then assessed the shape of the omega-3-PTB relationship with a penalised spline and conducted linear regression analyses within the linear sections of the relationship. RESULTS: Penalised spline analyses indicated that PTB rates decrease linearly with increasing omega-3 levels up to ~600 mg/day. Income-adjusted linear regression analysis among the countries in this exposure range indicated that the number of PTBs per 100 live births decreases by 1.5 (95% CI 2.8 to 0.3) for each 1 SD increase in omega-3 intake norms (383 mg/day). CONCLUSIONS: Taken with prior evidence for a causal association on the individual level, our findings indicate that omega-3 PUFA deficiency may be a widespread contributing factor in PTB risk. Consideration of baseline omega-3 PUFA levels is critical in the design of future interventions.

Iron-processing genotypes, nutrient intakes, and cadmium levels in the Normative Aging Study: Evidence of sensitive subpopulations in cadmium risk assessment.

BACKGROUND: Because iron and cadmium share common transport mechanisms, iron-processing protein variants such as HFE C282Y, HFE H63D, and Transferrin P570S may influence cadmium metabolism. Our aim was to evaluate associations between common HFE and Transferrin polymorphisms and toenail cadmium levels among older men. METHODS: In a longitudinal cohort of men age 51-97, the Normative Aging Study (NAS), we evaluated toenail cadmium concentrations and missense single nucleotide polymorphisms (SNPs) in the HFE and Transferrin genes. We fit age-adjusted models to estimate associations between genotypes and toenail cadmium concentrations. We then considered potential interactions with smoking status, hemoglobin, and nutritional intakes known to modulate cadmium absorption. For the significant interactions, we also evaluated genotype specific effect estimates. RESULTS: HFE and Transferrin genotypes were not associated with toenail cadmium concentrations in the main effect analyses, but there were significant interactions between HFE H63D and hemoglobin (pinteraction = 0.021), as well as HFE H63D and vitamin C intake (pinteraction = 0.048). Genotype specific effect estimates suggested: 1) an inverse relationship between hemoglobin and cadmium levels among HFE H63D homozygotes, and 2) an inverse relationship between vitamin C intake and cadmium levels that strengthens with the number of HFE H63D variant alleles a subject carries. CONCLUSIONS: These findings suggest that sensitive subpopulations defined by diet, hemoglobin level, and genotype may absorb more cadmium from their environment and thus should be considered in cadmium risk analyses. These findings are particularly relevant given the high prevalence of the H63D variant worldwide.

Transdisciplinary approaches enhance the production of translational knowledge.

The primary goal of translational research is to generate and apply knowledge that can improve human health. Although research conducted within the confines of a single discipline has helped us to achieve this goal in many settings, this unidisciplinary approach may not be optimal when disease causation is complex and health decisions are pressing. To address these issues, we suggest that transdisciplinary approaches can facilitate the progress of translational research, and we review publications that demonstrate what these approaches can look like. These examples serve to (1) demonstrate why transdisciplinary research is useful, and (2) stimulate a conversation about how it can be further promoted. While we note that open-minded communication is a prerequisite for germinating any transdisciplinary work and that epidemiologists can play a key role in promoting it, we do not propose a rigid protocol for conducting transdisciplinary research, as one really does not exist. These achievements were developed in settings where typical disciplinary and institutional barriers were surmountable, but they were not accomplished with a single predetermined plan. The benefits of cross-disciplinary communication are hard to predict a priori and a detailed research protocol or process may impede the realization of novel and important insights. Overall, these examples demonstrate that enhanced cross-disciplinary information exchange can serve as a starting point that helps researchers frame better questions, integrate more relevant evidence, and advance translational knowledge more effectively. Specifically, we discuss examples where transdisciplinary approaches are helping us to better explore, assess, and intervene to improve human health.

Maternal psychiatric disease and epigenetic evidence suggest a common biology for poor fetal growth.

BACKGROUND: We sought to identify and characterize predictors of poor fetal growth among variables extracted from perinatal medical records to gain insight into potential etiologic mechanisms. In this process we reevaluated a previously observed association between poor fetal growth and maternal psychiatric disease. METHODS: We evaluated 449 deliveries of >36 weeks gestation that occurred between 9/2008 and 9/2010 at the Women and Infants Hospital in Providence Rhode Island. This study group was oversampled for Small-for-Gestational-Age (SGA) infants and excluded Large-for-Gestational-Age (LGA) infants. We assessed the associations between recorded clinical variables and impaired fetal growth: SGA or Intrauterine Growth Restriction (IUGR) diagnosis. After validating the previously observed association between maternal psychiatric disease and impaired fetal growth we addressed weaknesses in the prior studies by explicitly considering antidepressant use and the timing of symptoms with respect to pregnancy. We then evaluated DNA methylation levels at 27 candidate loci in placenta from a subset of these deliveries (n = 197) to examine if epigenetic variation could provide insight into the mechanisms that cause this co-morbidity. RESULTS: Infants of mothers with prenatal psychiatric disease (Depression, Anxiety, OCD/Panic) had increased odds of poor fetal growth (ORadjusted = 3.36, 95%CI: 1.38-8.14). This relationship was similar among those who were treated with antidepressants (ORadjusted = 3.69, 95%CI: 1.31-10.45) and among those who were not (ORadjusted = 3.19, 95%CI: 1.30-7.83). Among those with a history of psychiatric disease but no active disease in pregnancy the ORadjusted was 0.45 (95%CI: 0.09-2.35). A locus near the transcription start site of the leptin receptor (cg21655790) had methylation levels that were decreased in the presence of: 1) SGA/IUGR, and 2) active but not resolved psychiatric disease (among mothers not on antidepressants). CONCLUSIONS: These results validate and further characterize the association between maternal psychiatric disease and poor fetal growth. Because the association appears to depend on active psychiatric disease, this suggests a transient and potentially modifiable pathophysiology. The molecular findings in this study suggest that altered leptin signaling may be involved in the biological mechanisms that link prenatal maternal psychiatric symptoms and poor fetal growth.

Diverse convergent evidence in the genetic analysis of complex disease: coordinating omic, informatic, and experimental evidence to better identify and validate risk factors.

In omic research, such as genome wide association studies, researchers seek to repeat their results in other datasets to reduce false positive findings and thus provide evidence for the existence of true associations. Unfortunately this standard validation approach cannot completely eliminate false positive conclusions, and it can also mask many true associations that might otherwise advance our understanding of pathology. These issues beg the question: How can we increase the amount of knowledge gained from high throughput genetic data? To address this challenge, we present an approach that complements standard statistical validation methods by drawing attention to both potential false negative and false positive conclusions, as well as providing broad information for directing future research. The Diverse Convergent Evidence approach (DiCE) we propose integrates information from multiple sources (omics, informatics, and laboratory experiments) to estimate the strength of the available corroborating evidence supporting a given association. This process is designed to yield an evidence metric that has utility when etiologic heterogeneity, variable risk factor frequencies, and a variety of observational data imperfections might lead to false conclusions. We provide proof of principle examples in which DiCE identified strong evidence for associations that have established biological importance, when standard validation methods alone did not provide support. If used as an adjunct to standard validation methods this approach can leverage multiple distinct data types to improve genetic risk factor discovery/validation, promote effective science communication, and guide future research directions.