Stephanie Ly

Genetic risk factors for orofacial clefts in Central Africans and Southeast Asians

Genome‐wide association studies (GWAS) for orofacial clefts have identified several susceptibility regions, but have largely focused on non‐Hispanic White populations in developed countries. We performed a targeted genome‐wide study of single nucleotide polymorphisms (SNPs) in exons using the Illumina HumanExome+ array with custom fine mapping of 16 cleft susceptibility regions in three underserved populations: Congolese (87 case‐mother, 210 control‐mother pairs), Vietnamese (131 case‐parent trios), and Filipinos (42 case‐mother, 99 control‐mother pairs). All cases were children with cleft lip with or without cleft palate. Families were recruited from local hospitals and parental exposures were collected using interviewer‐administered questionnaires. We used logistic regression models for case‐control analyses, family‐based association tests for trios, and fixed‐effect meta‐analyses to determine individual SNP effects corrected for multiple testing. Of the 16 known susceptibility regions tested, SNPs in four regions reached statistical significance in one or more of these populations: 1q32.2 (IRF6), 10q25.3 (VAX1), and 17q22 (NOG). Due to different linkage disequilibrium patterns, significant SNPs in these regions differed between the Vietnamese and Filipino populations from the index SNP selected from previous GWAS studies. Among Africans, there were no significant associations identified for any of the susceptibility regions. rs10787738 near VAX1 (P = 4.98E−3) and rs7987165 (P = 6.1E−6) were significant in the meta‐analysis of all three populations combined. These results confirm several known susceptibility regions and identify novel risk alleles in understudied populations.

Parental risk factors for oral clefts among Central Africans, Southeast Asians, and Central Americans

Background Several lifestyle and environmental exposures have been suspected as risk factors for oral clefts, although few have been convincingly demonstrated. Studies across global diverse populations could offer additional insight given varying types and levels of exposures. Methods We performed an international case–control study in the Democratic Republic of the Congo (133 cases, 301 controls), Vietnam (75 cases, 158 controls), the Philippines (102 cases, 152 controls), and Honduras (120 cases, 143 controls). Mothers were recruited from hospitals and their exposures were collected from interviewer‐administered questionnaires. We used logistic regression modeling to estimate odds ratios (OR) and 95% confidence intervals (CI). Results Family history of clefts was strongly associated with increased risk (maternal: OR = 4.7; 95% CI, 3.0–7.2; paternal: OR = 10.5; 95% CI, 5.9–18.8; siblings: OR = 5.3; 95% CI, 1.4–19.9). Advanced maternal age (5 year OR = 1.2; 95% CI, 1.0–1.3), pregestational hypertension (OR = 2.6; 95% CI, 1.3–5.1), and gestational seizures (OR = 2.9; 95% CI, 1.1–7.4) were statistically significant risk factors. Lower maternal (secondary school OR = 1.6; 95% CI, 1.2–2.2; primary school OR = 2.4, 95% CI, 1.6–2.8) and paternal education (OR = 1.9; 95% CI, 1.4–2.5; and OR = 1.8; 95% CI, 1.1–2.9, respectively) and paternal tobacco smoking (OR = 1.5, 95% CI, 1.1–1.9) were associated with an increased risk. No other significant associations between maternal and paternal factors were found; some environmental factors including rural residency, indoor cooking with wood, chemicals and water source appeared to be associated with an increased risk in adjusted models. Conclusion Our study represents one of the first international studies investigating risk factors for clefts among multiethnic underserved populations. Our findings suggest a multifactorial etiology including both maternal and paternal factors. Birth Defects Research (Part A) 103:863–879, 2015.

The Global Surgery Partnership: An Innovative Partnership for Education, Research, and Service.

PROBLEM An estimated two billion people worldwide lack access to adequate surgical care. Addressing surgical disparities requires both immediate relief efforts and long-term investments to improve access to care and surgical outcomes, train the next generation of surgical professionals, and expand the breadth of formative research in the field. While models exist for establishing short-term surgical missions in low- and middle-income countries, far less focus has been placed on models for multi-institutional partnerships that support the development of sustainable solutions. APPROACH In 2011, the Global Surgery Partnership (GSP) was founded by an established childrens hospital (Childrens Hospital Los Angeles), an academic medical center (University of Southern California), and a nonprofit organization (Operation Smile) to build oral cleft surgical capacity in resource-poor settings through education, research, and service. OUTCOMES Leveraging the strengths of each partner, the GSP supports three global health education programs for public health graduate students and surgical residents, including the Tsao Fellowship in Global Health; has initiated two international research projects on cleft lip and palate epidemiology; and has built upon Operation Smiles service provision. As of January 2015, Tsao fellows had operated on over 600 patients during 13 missions in countries including China, Vietnam, Mexico, and India. NEXT STEPS The GSP plans to conduct a formal evaluation and then to expand its programs. The GSP encourages other global health organizations and academic and medical institutions to engage with each other. The partnership described here provides a basic model for structuring collaborations in the global health arena.

The Tsao Fellowship in Global Health: A Model for International Fellowships in a Surgery Residency.

Objective:To present a model for integrated global health fellowships in plastic surgical residency training. Background:National surveys have found that North American surgical residents have significant interest in international training. While global health training opportunities exist, less than a third of these are housed within surgical residency programs; even fewer are designed specifically for plastic surgery residents. Methods:The Tsao Fellowship was created through a partnership between Operation Smile, Childrens Hospital Los Angeles, Shriners Hospital for Children, and the University of Southern California. Designed for Accreditation Council for Graduate Medical Education accredited plastic surgery residents between their third and fourth years of residency, the fellowship curriculum is completed over 24 months and divided into 3 areas: clinical research, international reconstructive surgery fieldwork, and the completion of a Master of Science in Clinical and Biomedical Investigations. Results:The Tsao Fellowship has matriculated 4 fellows: 3 have graduated from the program and 1 is in the current cycle. Fellows completed 4 to 7 international missions each cycle and have performed an aggregate total of 684 surgical procedures. Each fellow also conducted 2 to 6 research projects and authored several publications. All fellows continue to assume leadership roles within the field of global reconstructive surgery. Conclusions:Comprehensive global health fellowships provide invaluable opportunities beyond surgical residency. The Tsao Fellowship is a model for integrating international surgical training with global health research in plastic surgical residency that can be applied to other residency programs and different surgical specialties.

Menopause: A Contextualized Experience Across Social Structures

Menopause is a phenomenon experienced by women as they approach middle age, marking the end of menstruation and reproduction. Throughout history, menopause has been classified in negative terms as a malady and decay of femininity necessitating a cure, which led to the controversial development of hormone replacement therapy. Feminists and activists challenged existing stereotypes and emphasized menopause as a natural transition. There is still little consensus on universal menopause symptoms since wide variations are reported across geographic regions and cultures. These differences can be better examined via individual menopausal experiences, which are unique and shaped by attitudes and expectations. Macro-level structures often place psychosocial constraints on individual women imposing roles after menopause or creating expectations of common symptoms. This chapter applies three theoretical frameworks to the menopausal experience. The biomedical model portrays menopause as a result of biological pathways with clear diagnoses of menopausal stages and is widely used by physicians. The life course perspective views menopause as a lifelong process that is shaped by the current time period with early life advantages or disadvantages that affect women as they enter their menopausal years. The biopsychosocial model integrates womens experiences of menopause into a hierarchy of structures. Each woman is shaped by microlevel factors like genetics and body functions while also influenced by macro-level structures within her family or society. As the number of women experiencing menopause rises with emerging demographic shifts, special consideration to individual and global experiences of menopause should be integrated to advance well-being.

Paternal Risk Factors for Oral Clefts in Northern Africans, Southeast Asians, and Central Americans

While several studies have investigated maternal exposures as risk factors for oral clefts, few have examined paternal factors. We conducted an international multi-centered case–control study to better understand paternal risk exposures for oral clefts (cases = 392 and controls = 234). Participants were recruited from local hospitals and oral cleft repair surgical missions in Vietnam, the Philippines, Honduras, and Morocco. Questionnaires were administered to fathers and mothers separately to elicit risk factor and family history data. Associations between paternal exposures and risk of clefts were assessed using logistic regression adjusting for potential confounders. A father’s personal/family history of clefts was associated with significantly increased risk (adjusted OR: 4.77; 95% CI: 2.41–9.45). No other significant associations were identified for other suspected risk factors, including education (none/primary school v. university adjusted OR: 1.29; 95% CI: 0.74–2.24), advanced paternal age (5-year adjusted OR: 0.98; 95% CI: 0.84–1.16), or pre-pregnancy tobacco use (adjusted OR: 0.96; 95% CI: 0.67–1.37). Although sample size was limited, significantly decreased risks were observed for fathers with selected occupations. Further research is needed to investigate paternal environmental exposures as cleft risk factors.

Abstract P23: THE INTERNATIONAL FAMILY STUDY

Introduction: Oral-facial clefts are congenital birth defects de ned by a gap in the lip, palate or both. The clinical burden of this condition varies widely by sex, ethnicity, race, geography and socio-economic status, suggesting that maternal, environmental and genetic risk factors contribute to the etiology. Epidemiologic studies and experimental data suggest that maternal exposures during gestation may be associated with the occurrence of oral clefts, including tobacco smoke, alcohol, poor nutrition, viral infections, medications and teratogens in the home and workplace. Genome-wide association studies have reported a few genetic variants associated with oral clefts, but none have reported on risk factors in minority populations, or considered the combined clinical effect of maternal exposures. We have conducted a case-trio/case-control study to investigate genetic and prenatal risk factors associated with oral cleft risk in children of underserved populations.