Our Research

INTRODUCTION: Neonatal mortality remains disproportionately high in sub-Saharan Africa, where an estimated 27 neonatal deaths per 1,000 live births occur annually. Infections, including sepsis and meningitis, account for a substantial proportion of these deaths, while neural tube defects (NTDs) contribute significantly to both neonatal mortality and long-term disability. Existing surveillance systems in the region are predominantly facility-based, missing the substantial proportion of births and deaths that occur in the community. Population-based surveillance platforms that capture community-level data are urgently needed to generate accurate incidence estimates, identify modifiable risk factors, and guide evidence-based interventions.

COHORT DESCRIPTION: The Consortium to Reduce Infant Mortality (CONRIM) is a multi-institutional partnership among Ugandan physicians and scientists, Yale University, Penn State University, Boston Children's Hospital/Harvard Medical School, and Uganda's National Planning Authority. CONRIM conducts prospective, community-based neonatal surveillance within the Busoga Kingdom in eastern Uganda. A network of 813 trained Village Health Team members conducts household-level visits using a structured Open Data Kit (ODK)-based mobile questionnaire to capture every birth, assess for danger signs of possible serious bacterial infection (pSBI), screen for NTDs, and record maternal nutrition and folic acid use, water, sanitation and hygiene (WASH) conditions, and health care utilization.

FINDINGS TO DATE: Since surveillance began in June 2025, the platform has registered approximately 22,200 household submissions and over 5,700 newborn encounters across the Jinja District (population 660,000). Early data have identified higher than expected rates of infants with NTDs including encephalocele and spina bifida; documented folic acid non-use in before and during most pregnancies; characterized WASH conditions in birthplaces; and mapped geospatial hotspots of neonatal infection risk in northeastern rural subcounties. Prospective 28-day follow-up of all live births has demonstrated a neonatal mortality rate of 21.5 per 1000 live births. A real-time data quality monitoring system with 21 automated quality control flags maintains a 99% clean-record rate.

FUTURE PLANS: Ongoing and planned activities include laboratory-based confirmation of neonatal sepsis via blood culture and cerebrospinal fluid analysis with polymerase chain reaction capacity, portable neuroimaging for NTDs, environmental sampling, genomic studies of folate metabolism pathway genes, linkage with facility-based records at Jinja Regional Referral Hospital and Mulago National Referral Hospital, and community-level interventions informed by surveillance findings.

KEY MESSAGES: What is already known on this topic: Neonatal mortality remains disproportionately high in sub-Saharan Africa, with sepsis and neural tube defects (NTDs) among the leading preventable causes. Existing surveillance systems are predominantly facility-based and fail to capture births, deaths, and environmental exposures occurring at the community level. Emerging approaches in digital health, geospatial analytics, and pathogen genomics have demonstrated potential to enhance infectious disease surveillance, but these have rarely been integrated into population-based neonatal monitoring systems in low-resource settings.What this study adds: The Consortium to Reduce Infant Mortality (CONRIM) is a multidisciplinary initiative designed to develop scalable, population-based systems for understanding and reducing neonatal mortality through integrated epidemiologic, environmental, and biologic data. This paper describes one implementation of the CONRIM framework in the Busoga Kingdom of eastern Uganda, where a network of 813 trained Village Health Team members conducts longitudinal, community-based surveillance of births, neonatal outcomes, NTDs, maternal nutrition (including folic acid use), water, sanitation and hygiene (WASH) conditions, and care-seeking behaviour. This implementation integrates: real-time digital data capture with automated quality control,geospatial information systems (GIS) and remote sensing to characterize environmental risk factors,population-level genomic and metagenomic sampling to investigate host and pathogen factors, anda One Health framework linking human, animal, and environmental exposures. Early findings highlight high data completeness, geospatial clustering of neonatal infection risk, low preconception folic acid use, and identification of NTD cases not captured by facility-based systems.How this study might affect research, practice, or policy: This study demonstrates the feasibility of implementing a community-based, real-time neonatal surveillance system within an existing community health worker network in a low-resource setting. By integrating geospatial, genomic, and environmental data within a unified platform, the CONRIM framework enables more precise identification of drivers of neonatal morbidity and mortality.The approach supports targeted public health interventions, including geographically informed infection control strategies, improved referral pathways, and evidence generation for folic acid fortification policies. More broadly, CONRIM provides a scalable infrastructure for future interventional studies and precision public health strategies aimed at reducing neonatal mortality.

Congenital heart disease (CHD) affects  1% of live births, yet the genetic basis of many cases remains unresolved. Uniparental disomy (UPD), the inheritance of both homologous chromosomes from one parent, is often overlooked. We developed TrioMix-UPD, an integrated short- and long-read sequencing framework for UPD detection and classification. Applying it to 3,740 CHD trios, we identified 12 UPD events, representing a 6.57-fold enrichment relative to the general population. Both advanced maternal age and enrichment of rare inherited variants in synaptonemal complex genes implicated meiotic chromosome segregation defects in UPD risk. Within UPD regions, we identified pathogenic homozygous variants in PIEZO1 and GLYR1 and nominate MESD as a novel CHD candidate gene. Functional studies in zebrafish and human cells recapitulated patient-specific cardiac phenotypes. Differential methylation analyses implicated imprinting dysregulation, including at the Prader-Willi critical region. Collectively, these findings establish UPD as an underrecognized contributor to CHD.

BACKGROUND: Children with heart disease face competing risks of thrombosis and bleeding. Antiplatelet agents are widely used, but clinical effectiveness and safety may vary with pharmacogenomic variants. We evaluated bleeding and thromboembolic outcomes and explored pharmacogenomic associations in a pediatric cardiac cohort.

METHODS: Single-center, retrospective study of patients prescribed aspirin or clopidogrel during admissions (2011-2020). We abstracted clinical characteristics, pharmacodynamic testing, and adverse events while prescribed the antiplatelet agent through July 2021. Pharmacogenomic variants relevant to aspirin and clopidogrel metabolism/function (including CYP2C19 haplotypes and selected aspirin response loci) were called from existing genomic data. Outcomes included major bleeding and thromboembolism (TE) as well as pharmacodynamic aspirin "resistance." Analyses were exploratory.

RESULTS: We included 105 patients treated with aspirin with VerifyNow pharmacodynamic and pharmacogenomic variant data and 49 clopidogrel-treated patients with genetic data. Major bleeding occurred in 5% (aspirin) and 16% (clopidogrel); TE occurred in 12% and 8% of patients, respectively. On aspirin, bleeding was more frequent with renal (40% vs. 2%, p = 0.011) or hepatic dysfunction (20% vs. 0%, p = 0.048); TE was associated with younger age, lower weight, and single-ventricle physiology. On clopidogrel, bleeding was associated with older age/greater weight and renal dysfunction. No association was observed across CYP2C19 phenotypes and clopidogrel outcomes. No poor metabolizers were identified in this small cohort. Pharmacodynamic aspirin "resistance" was seen in 23% and was more common in females, with no association identified with TE. A P2RY1 variant (rs1065776-CT) was associated with the composite aspirin outcome of pharmacodynamic resistance and/or TE.

CONCLUSIONS: Clinically important bleeding and TE events were common in pediatric cardiac patients on antiplatelets, with organ dysfunction, age, and physiology emerging as key associations. Pharmacogenomic variants were frequent; a candidate P2RY1 signal warrants validation. Pediatric antiplatelet management and relationships with outcomes are complex, supporting the need for prospective studies integrating pharmacogenomic variant analyses with standardized pharmacodynamic testing.

Folate deficiency is associated with an increased risk of conotruncal heart defects (CTHD), but interactions with genetic factors remain unclear. Our objective was to investigate genome-wide associations between genetic variants and birth before versus after universal folic acid fortification among children with CTHD and other heart defects. Genetic sequencing data were available through the Pediatric Cardiac Genomics Consortium. Sequencing data were aligned to the human reference genome (GRCh38/hg38) and jointly processed to ensure uniform variant detection and minimize batch effects. Analyses were restricted to individuals with European-inferred genetic ancestry. GWAS models were implemented to explore the association of common variants with fortification eras among all participants (n=1285), the subset of individuals with CTHD (n=534), and the remaining individuals with other heart defects (n=751). Functional enrichment was assessed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Among the full analytic group, eight loci had at least two nominally-enriched variants before compared to after fortification. Among the subset with CTHD, two variants located in DHRS3 (rs7551703, OR 2.10, and rs6541043, OR 2.21) and four variants located in PPARGC1β were nominally enriched after fortification (OR 4.47-4.51). Enriched biological pathway terms were consistent with cardiac developmental processes. In summary, this study examined the association between folic acid fortification and genetic risk for CTHD and other heart defects and identified associations with fortification era that may suggest some shift in risk following fortification. Identified pathways suggest gene-nutrient interactions may modulate cardiac developmental pathways, underscoring the relationship between maternal folate status and cardiovascular development.

BACKGROUND: Children with congenital heart disease (CHD) experience neurodevelopmental challenges, arising in part from altered brain maturation beginning in utero. There are currently no prenatal interventions to mitigate this risk. Foetal CHD is associated with alterations in maternal blood pressure (BP), for which therapies are available, so we investigated associations between maternal BP, foetal cerebral haemodynamics, and brain growth in foetuses with and without CHD.

METHODS: Our single-centre retrospective cohort study first analysed maternal BP during pregnancy stratified by foetal CHD (n = 494), other foetal anomalies (n = 769), or no foetal anomalies (n = 111). We then performed a prospective study linking maternal BP with foetal brain MRI and cerebral and umbilical Doppler measures in pregnancies with foetal CHD (n = 97 MRI; 121 Doppler) and those with no foetal anomalies (n = 111 MRI; 86 Doppler).

FINDINGS: Mothers carrying a foetus with CHD showed a distinct BP profile compared with unaffected controls and non-CHD foetal anomaly pregnancies. In CHD pregnancies, but not in controls, lower maternal diastolic BP was associated with lower cerebrovascular resistance, lower cerebroplacental flow ratio, and an attenuated reduction in foetal cortical surface area in sensorimotor, frontal and temporal cortical regions.

INTERPRETATION: Lower maternal diastolic BP may reflect adaptive maternal-foetal circulatory coupling that enhances foetal cerebral perfusion and mitigates cortical growth impairment in CHD. We observe a link between maternal haemodynamics and foetal brain maturation in CHD, warranting further exploration in interventional studies.

FUNDING: Supported by the NINDS (R01NS114087, K23NS101120), NIBIB (R01EB031170), NHLBI (K08HL157653), AAN Clinical Research Training Fellowship, BBRF Young Investigator Awards, and the Farb Family Fund.