Prophylactic use of cardiac medications for delay of left ventricular dysfunction in Duchenne muscular dystrophy.

BACKGROUND: Epidemiological support for prophylactic treatment of left ventricular dysfunction (LVD) in Duchenne muscular dystrophy is limited. We used retrospective, population-based surveillance data from the Muscular Dystrophy Surveillance, Tracking and Research Network to evaluate whether prophylaxis delays LVD onset. METHODS: We analyzed 455 males born during 1982-2009. Age at first abnormal echocardiogram (ejection fraction <55% or shortening fraction <28%) determined LVD onset. Prophylaxis was defined as cardiac medication use at least 1 year prior to LVD. Corticosteroid use was also coded. Kaplan-Meier curve estimation and Cox Proportional Hazard modeling with time-varying covariates describe associations. RESULTS: LVD was identified among 40.7%; average onset age was 14.2 years. Prophylaxis was identified for 20.2% and corticosteroids for 57.4%. Prophylaxis showed delayed LVD onset (p < .001) and lower hazard of dysfunction (adjusted hazard ratio [aHR] = 0.39, 95%CL = 0.22, 0.65) compared to untreated. Compared to no treatment, continuous corticosteroids only (aHR = 1.01, 95%CL = 0.66, 1.53) and prophylaxis only (aHR = 0.67, 95%CL = 0.25, 1.50) were not cardioprotective, but prophylaxis plus continuous corticosteroids were associated with lower hazard of dysfunction (aHR = 0.37, 95%CL = 0.15, 0.80). CONCLUSIONS: Proactive cardiac treatment and monitoring are critical aspects of managing Duchenne muscular dystrophy. Consistent with clinical care guidelines, this study supports clinical benefit from cardiac medications initiated prior to documented LVD and suggests further benefit when combined with corticosteroids.

Trends in congenital clubfoot prevalence and co-occurring anomalies during 1994-2021 in Denmark: a nationwide register-based study.

BACKGROUND: Congenital talipes equinovarus (clubfoot) is a common musculoskeletal anomaly, with a suspected multifactorial etiopathogenesis. Herein, we used publicly available data to ascertain liveborn infants with clubfoot delivered in Denmark during 1994-2021, and to classify co-occurring congenital anomalies, estimate annual prevalence, and compare clubfoot occurrence with maternal smoking rates, a commonly reported risk factor. Characterizing this nationwide, liveborn cohort provides a population-based resource for etiopathogenic investigations and life course surveillance. METHODS: This case-cohort study used data from the Danish National Patient Register and Danish Civil Registration System, accessed through the publicly available Danish Biobank Register, to identify 1,315,282 liveborn infants delivered during 1994-2021 in Denmark to Danish parents. Among these, 2,358 infants (65.1% male) were ascertained with clubfoot and classified as syndromic (co-occurring chromosomal, genetic, or teratogenic syndromes) and nonsyndromic (isolated or co-occurring multiple congenital anomalies [MCA]). Annual prevalence estimates and corresponding 95% confidence intervals (CIs) for children with nonsyndromic clubfoot were estimated using Poisson regression and compared with population-based, maternal annual smoking rates obtained from publicly available resources. RESULTS: Infants most often presented with nonsyndromic clubfoot (isolated = 88.6%; MCA = 11.4%); limb and heart anomalies were the most frequently identified MCAs. Prevalence (per 1,000 liveborn infants) was 1.52 (CI 1.45-1.58) for isolated and 0.19 (CI 0.17-0.22) for MCA clubfoot. Prevalence estimates for both isolated and MCA clubfoot remained relatively stable during the study period, despite marked decreases in population-based maternal smoking rates. CONCLUSIONS: From 1994 to 2021, prevalence of nonsyndromic clubfoot in Denmark was relatively stable. Reduction in population-level maternal smoking rates did not seem to impact prevalence estimates, providing some support for the suspected multifactorial etiopathogenesis of this anomaly. This nationwide, liveborn cohort, ascertained and clinically characterized using publicly available data from the Danish Biobank Register, provides a population-based clinical and biological resource for future etiopathogenic investigations and life course surveillance.

Is gastroschisis associated with county-level socio-environmental quality during pregnancy?

BACKGROUND: Gastroschisis prevalence more than doubled between 1995 and 2012. While there are individual-level risk factors (e.g., young maternal age, low body mass index), the impact of environmental exposures is not well understood. METHODS: We used the U.S. Environmental Protection Agency's Environmental Quality Index (EQI) as a county-level estimate of cumulative environmental exposures for five domains (air, water, land, sociodemographic, and built) and overall from 2006 to 2010. Adjusted odds ratios (aOR) and 95% confidence interval (CI) were estimated from logistic regression models between EQI tertiles (better environmental quality (reference); mid; poorer) and gastroschisis in the National Birth Defects Prevention Study from births delivered between 2006 and 2011. Our analysis included 594 cases with gastroschisis and 4105 infants without a birth defect (controls). RESULTS: Overall EQI was modestly associated with gastroschisis (aOR [95% CI]: 1.29 [0.98, 1.71]) for maternal residence in counties with poorer environmental quality, compared to the reference (better environmental quality). Within domain-specific indices, only the sociodemographic domain (aOR: 1.51 [0.99, 2.29]) was modestly associated with gastroschisis, when comparing poorer to better environmental quality. CONCLUSIONS: Future work could elucidate pathway(s) by which components of the sociodemographic domain or possibly related psychosocial factors like chronic stress potentially contribute to risk of gastroschisis.

Are individual-level risk factors for gastroschisis modified by neighborhood-level socioeconomic factors?

BACKGROUND: Two strong risk factors for gastroschisis are young maternal age (<20 years) and low/normal pre-pregnancy body mass index (BMI), yet the reasons remain unknown. We explored whether neighborhood-level socioeconomic position (nSEP) during pregnancy modified these associations. METHODS: We analyzed data from 1269 gastroschisis cases and 10,217 controls in the National Birth Defects Prevention Study (1997-2011). To characterize nSEP, we applied the neighborhood deprivation index and used generalized estimating equations to calculate odds ratios and relative excess risk due to interaction. RESULTS: Elevated odds of gastroschisis were consistently associated with young maternal age and low/normal BMI, regardless of nSEP. High-deprivation neighborhoods modified the association with young maternal age. Infants of young mothers in high-deprivation areas had lower odds of gastroschisis (adjusted odds ratio [aOR]: 3.1, 95% confidence interval [CI]: 2.6, 3.8) than young mothers in low-deprivation areas (aOR: 6.6; 95% CI: 4.6, 9.4). Mothers of low/normal BMI had approximately twice the odds of having an infant with gastroschisis compared to mothers with overweight/obese BMI, regardless of nSEP (aOR range: 1.5-2.3). CONCLUSION: Our findings suggest nSEP modified the association between gastroschisis and maternal age, but not BMI. Further research could clarify whether the modification is due to unidentified biologic and/or non-biologic factors.

Neighborhood-level Socioeconomic Position During Early Pregnancy and Risk of Gastroschisis.

BACKGROUND: Neighborhood-level socioeconomic position has been shown to influence birth outcomes, including selected birth defects. This study examines the un derstudied association between neighborhood-level socioeconomic position during early pregnancy and the risk of gastroschisis, an abdominal birth defect of increasing prevalence. METHODS: We conducted a case-control study of 1,269 gastroschisis cases and 10,217 controls using data from the National Birth Defects Prevention Study (1997-2011). To characterize neighborhood-level socioeconomic position, we conducted a principal component analysis to construct two indices-Neighborhood Deprivation Index (NDI) and Neighborhood Socioeconomic Position Index (nSEPI). We created neighborhood-level indices using census socioeconomic indicators corresponding to census tracts associated with addresses where mothers lived the longest during the periconceptional period. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with multiple imputations for missing data and adjustment for maternal race-ethnicity, household income, education, birth year, and duration of residence. RESULTS: Mothers residing in moderate (NDI Tertile 2 aOR = 1.23; 95% CI = 1.03, 1.48 and nSEPI Tertile 2 aOR = 1.24; 95% CI = 1.04, 1.49) or low socioeconomic neighborhoods (NDI Tertile 3 aOR = 1.28; 95% CI = 1.05, 1.55 and nSEPI Tertile 3 aOR = 1.32, 95% CI = 1.09, 1.61) were more likely to deliver an infant with gastroschisis compared with mothers residing in high socioeconomic neighborhoods. CONCLUSIONS: Our findings suggest that lower neighborhood-level socioeconomic position during early pregnancy is associated with elevated odds of gastroschisis. Additional epidemiologic studies may aid in confirming this finding and evaluating potential mechanisms linking neighborhood-level socioeconomic factors and gastroschisis.

Maternal dietary caffeine consumption and risk of birth defects in the National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Caffeine consumption is common during pregnancy, but published associations with birth defects are mixed. We updated estimates of associations between prepregnancy caffeine consumption and 48 specific birth defects from the National Birth Defects Prevention Study (NBDPS) for deliveries from 1997 to 2011. METHODS: NBDPS was a large population-based case-control study conducted in 10 U.S. states. We categorized self-reported total dietary caffeine consumption (mg/day) from coffee, tea, soda, and chocolate as: <10, 10 to <100, 100 to <200, 200 to <300, and ≥ 300. We used logistic regression to estimate adjusted odds ratios (aORs [95% confidence intervals]). Analyses for defects with ≥5 exposed case children were adjusted for maternal race/ethnicity, age at delivery, body mass index, early pregnancy cigarette smoking and alcohol use, and study site. RESULTS: Our analysis included 30,285 case and 11,502 control children, with mothers of 52% and 54%, respectively, reporting consuming <100 mg caffeine, and 11% of mothers of both cases and controls reported consuming ≥300 mg per day. Low (10 to <100 mg/day) levels of prepregnancy caffeine consumption were associated with statistically significant increases in aORs (1.2-1.7) for 10 defects. Associations with high (≥300 mg/day) levels of caffeine were generally weaker, except for craniosynostosis and aortic stenosis (aORs = 1.3 [1.1-1.6], 1.6 [1.1-2.3]). CONCLUSIONS: Given the large number of estimates generated, some of the statistically significant results may be due to chance and thus the weakly increased aORs should be interpreted cautiously. This study supports previous observations suggesting lack of evidence for meaningful associations between caffeine consumption and the studied birth defects.

Racial and Ethnic Differences in Timing of Diagnosis and Clinical Services Received in Duchenne Muscular Dystrophy.

INTRODUCTION: Racial/ethnic differences in diagnostic and treatment services have been identified for a range of health conditions and outcomes. The current study aimed to analyze whether there are racial/ethnic differences in the timing of diagnostic testing and treatments for males with Duchenne muscular dystrophy (DMD). METHODS: Diagnostic and clinical data for male individuals with DMD born during 1990-2010 were analyzed from eight sites (Arizona, Colorado, Georgia, Iowa, Piedmont Region of North Carolina, Western New York, South Carolina, and Utah) of the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Seven milestones related to diagnosis/treatment experiences were selected as outcomes. Times to each milestone were estimated and compared by four racial/ethnic groups using Kaplan-Meier estimation and Cox proportional-hazards models. Times between initial evaluation or diagnostic testing and later milestones were also compared by race/ethnicity. RESULTS: We identified 682 males with definite or probable DMD of whom 61.7% were non-Hispanic white, 20.5% Hispanic, 10.6% other, and 7.2% non-Hispanic black. Seven milestone events were studied (initial evaluation, first neurology/neuromuscular visit, diagnosis, corticosteroid treatment first offered, corticosteroid treatment started, first electrocardiogram or echocardiogram, and first pulmonary function test). The first five milestone events occurred at an older age for non-Hispanic black individuals compared to non-Hispanic white individuals. Time to first offering of corticosteroids and initiation of corticosteroid therapy was later for Hispanic individuals compared to non-Hispanic white individuals. When accounting for timing of initial evaluation/diagnosis, offering of corticosteroids continued to occur later, but first pulmonary testing occurred earlier, among Hispanic individuals compared to non-Hispanic whites. No significant delays remained for non-Hispanic black individuals after accounting for later initial evaluation/diagnosis. CONCLUSION: We described racial/ethnic differences in ages at selected diagnostic and treatment milestones. The most notable differences were significant delays for five of seven milestones in non-Hispanic black individuals, which appeared to be attributable to later initial evaluation/diagnosis. Findings for Hispanic individuals were less consistent. Efforts to address barriers to early evaluation and diagnosis for non-Hispanic black children with DMD may promote more timely initiation of recommended disease monitoring and interventions.

Influenza vaccination during pregnancy and risk of selected major structural congenital heart defects, National Birth Defects Prevention Study 2006-2011.

BACKGROUND: Although results from studies of first-trimester influenza vaccination and congenital heart defects (CHDs) have been reassuring, data are limited for specific CHDs. METHODS: We assessed associations between reported maternal influenza vaccination, 1 month before pregnancy (B1) through end of third pregnancy month (P3), and specific CHDs using data from a multisite, population-based case-control study. Analysis included 2,982 case children diagnosed with a simple CHD (no other cardiac involvement with or without extracardiac defects) and 4,937 control children without a birth defect with estimated delivery dates during 2006-2011. For defects with ≥5 exposed case children, we used logistic regression to estimate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusting for estimated delivery year and season; plurality; and maternal age at delivery, race/ethnicity, low folate intake, and smoking and alcohol use during B1P3. RESULTS: Overall, 124 (4.2%) simple CHD case mothers and 197 (4.0%) control mothers reported influenza vaccination from 1 month before through the third pregnancy month. The aOR for any simple CHD was 0.97 (95% CI: 0.76-1.23). Adjusted ORs for specific simple CHDs ranged from 0.62 for hypoplastic left heart syndrome to 2.34 for total anomalous pulmonary venous return (TAPVR). All adjusted CIs included the null except for TAPVR. CONCLUSIONS: Although we cannot fully exclude that exposure misclassification may have masked risks for some CHDs, findings add to existing evidence supporting the safety of inactivated influenza vaccination during pregnancy. The TAPVR result may be due to chance, but it may help inform future studies.

Prepregnancy exposure to dietary arsenic and congenital heart defects.

INTRODUCTION: Arsenic crosses the placenta and accumulates in fetal tissues. In the United States, diet is the predominant route of arsenic exposure, but epidemiologic data are sparse regarding this exposure and development of birth defects. Using data from a large case-control study, we explored associations between maternal dietary arsenic exposure and congenital heart defects (CHDs), the most prevalent birth defects. METHODS: We used maternal self-reported dietary assessments and arsenic concentration estimates in food items to estimate average daily exposure to dietary arsenic during the year before pregnancy for mothers of 10,446 unaffected control children and 6,483 case children diagnosed with CHDs. Using tertiles of dietary exposure to total arsenic (all species) and inorganic arsenic, we applied logistic regression analysis to estimate associations for middle and high tertiles, compared with the low tertile. RESULTS: Positive associations (odds ratio [OR] ≥ 1.2) for total arsenic were observed in both tertiles for perimembranous ventricular septal defect (VSD) and high tertile only for double outlet right ventricle-transposition of the great arteries (DORV-TGA), partial anomalous pulmonary venous return (PAPVR), and tricuspid atresia. Positive associations were also observed in both tertiles (tricuspid atresia) and high tertile only (DORV-TGA, conoventricular VSD, PAPVR, and pulmonary atresia) for inorganic arsenic. Most remaining associations were near or below unity. DISCUSSION: Exploration of maternal dietary exposure to total and inorganic arsenic and CHDs produced few positive associations but was limited by available food item concentrations. Future research requires expanded collection of dietary data, improved estimates of concentrations, and consideration of nondietary sources of arsenic exposure.

Maternal cigarette smoking and alcohol consumption and congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) occurs when abnormal diaphragm development allows herniation of abdominal organs into the thoracic cavity. Its etiopathogenesis is not well understood, but cigarette smoking and alcohol exposure may impact diaphragm development. Using data from a large, population-based case-control study, we examined associations between maternal cigarette smoking and alcohol consumption and CDH in offspring. METHODS: We analyzed maternal interview reports of cigarette smoking and alcohol consumption during early pregnancy for 831 children with CDH and 11,416 children without birth defects with estimated dates of delivery during 1997-2011. Generalized linear mixed effects models with a random intercept for study site were used to estimate associations between measures of exposure to smoking (any, type, frequency, duration) and alcohol (any, quantity, frequency, variability, type) for all CDH combined and selected subtypes (Bochdalek and Morgagni). RESULTS: Mothers of 280 (34.0%) case and 3,451 (30.3%) control children reported early pregnancy exposure to cigarette smoking. Adjusted odds ratios for all CDH were increased for any (1.3; 95% confidence interval 1.1-1.5), active (1.3, 1.0-1.7), and passive (1.4, 1.1-1.7) smoking. Early pregnancy alcohol consumption was reported by mothers of 286 (34.9%) case and 4,200 (37.0%) control children; odds were near the null for any consumption (0.9, 0.8-1.1) and consumption with (0.9, 0.7, 1.1) or without (0.9, 0.8, 1.1) binging. Estimates for smoking and alcohol tended to be higher for Bochdalek CDH and Morgagni CDH than those for all CDH. CONCLUSIONS: Findings suggest that maternal early pregnancy exposure to cigarette smoking, but less so to alcohol consumption, contributes to CDH. These findings need to be replicated in additional large studies that use systematic case ascertainment and classification, detailed exposure assessment, and examine subtype-specific associations.

Pre-pregnancy exposure to arsenic in diet and non-cardiac birth defects.

OBJECTIVES: To explore associations between maternal pre-pregnancy exposure to arsenic in diet and non-cardiac birth defects. DESIGN: This is a population-based, case-control study using maternal responses to a dietary assessment and published arsenic concentration estimates in food items to calculate average daily total and inorganic arsenic exposure during the year before pregnancy. Assigning tertiles of total and inorganic arsenic exposure, logistic regression analysis was used to estimate OR for middle and high tertiles, compared to the low tertile. SETTING: US National Birth Defects Prevention Study, 1997-2011. PARTICIPANTS: Mothers of 10 446 children without birth defects and 14 408 children diagnosed with a non-cardiac birth defect. RESULTS: Maternal exposure to total dietary arsenic in the middle and high tertiles was associated with a threefold increase in cloacal exstrophy, with weak positive associations (1·2-1·5) observed either in both tertiles (intercalary limb deficiency) or the high tertile only (encephalocele, glaucoma/anterior chamber defects and bladder exstrophy). Maternal exposure to inorganic arsenic showed mostly weak, positive associations in both tertiles (colonic atresia/stenosis, oesophageal atresia, bilateral renal agenesis/hypoplasia, hypospadias, cloacal exstrophy and gastroschisis), or the high (glaucoma/anterior chamber defects, choanal atresia and intestinal atresia stenosis) or middle (encephalocele, intercalary limb deficiency and transverse limb deficiency) tertiles only. The remaining associations estimated were near the null or inverse. CONCLUSIONS: This exploration of arsenic in diet and non-cardiac birth defects produced several positive, but mostly weak associations. Limitations in exposure assessment may have resulted in exposure misclassification. Continued research with improved exposure assessment is recommended to identify if these associations are true signals or chance findings.

Selected clinical and demographic factors and all-cause mortality among individuals with Duchenne muscular dystrophy in the Muscular Dystrophy Surveillance, Tracking, and Research Network.

Population-based estimates of survival among individuals with Duchenne muscular dystrophy (DMD) living in the United States are lacking. It is also unclear whether the association between glucocorticoid use and all-cause mortality persists in the context of other common treatments (cardiac medication, cough-assist, bilevel positive airway pressure, and scoliosis surgery) observed to delay mortality. Among 526 individuals identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network, the estimated median survival time from birth was 23.7 years. Current glucocorticoid users had a lower hazard of mortality than non-users. Individuals who ever had scoliosis surgery had a lower hazard of mortality than individuals who did not have scoliosis surgery. Individuals who ever used cough assist had a lower hazard of mortality than individuals who never used cough assist. Non-Hispanic Black individuals had a higher hazard of mortality than non-Hispanic White individuals. No differences in hazards of mortality were observed between ever versus never use of cardiac medication and ever versus never use of bilevel positive airway pressure. The glucocorticoid observation is consistent with the 2018 Care Considerations statement that glucocorticoid use continues in the non-ambulatory phase. Our observations may inform the clinical care of individuals living with DMD.

Influenza vaccination during pregnancy and risk of selected major structural noncardiac birth defects, National Birth Defects Prevention Study 2006-2011.

PURPOSE: To assess associations between influenza vaccination during etiologically-relevant windows and selected major structural non-cardiac birth defects. STUDY DESIGN: We analyzed data from the National Birth Defects Prevention Study, a multisite, population-based case-control study, for 8233 case children diagnosed with a birth defect and 4937 control children without a birth defect with delivery dates during 2006-2011. For all analyses except for neural tube defects (NTDs), we classified mothers who reported influenza vaccination 1 month before through the third pregnancy month as exposed; the exposure window for NTDs was 1 month before through the first pregnancy month. For defects with five or more exposed case children, we used logistic regression to estimate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusting for estimated delivery year and season; plurality; maternal age, race/ethnicity, smoking and alcohol use, low folate intake; and, for NTDs, folate antagonist medications. RESULTS: There were 334 (4.1%) case and 197 (4.0%) control mothers who reported influenza vaccination from 1 month before through the third pregnancy month. Adjusted ORs ranged from 0.53 for omphalocele to 1.74 for duodenal atresia/stenosis. Most aORs (11 of 19) were ≤1 and all adjusted CIs included the null. The unadjusted CIs for two defects, hypospadias and craniosynostosis, excluded the null. These estimates were attenuated upon covariate adjustment (hypospadias aOR: 1.25 (95% CI 0.89, 1.76); craniosynostosis aOR: 1.23 (95% CI: 0.88, 1.74)). CONCLUSIONS: Results for several non-cardiac major birth defects add to the existing evidence supporting the safety of inactivated influenza vaccination during pregnancy. Under-reporting of vaccination may have biased estimates downward.

Time to diagnosis of Duchenne muscular dystrophy remains unchanged: Findings from the Muscular Dystrophy Surveillance, Tracking, and Research Network, 2000-2015.

INTRODUCTION/AIMS: With current and anticipated disease-modifying treatments, including gene therapy, an early diagnosis for Duchenne muscular dystrophy (DMD) is crucial to assure maximum benefit. In 2009, a study from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) showed an average diagnosis age of 5 years among males with DMD born from January 1, 1982 to December 31, 2000. Initiatives were implemented by the US Centers for Disease Control and Prevention (CDC) and patient organizations to reduce time to diagnosis. We conducted a follow-up study in a surveillance cohort born after January 1, 2000 to determine whether there has been an improvement in time to diagnosis. METHODS: We assessed the age of diagnosis among males with DMD born from January 1, 2000 to December 31, 2015 using data collected by six US MD STARnet surveillance sites (Colorado, Iowa, western New York State, the Piedmont region of North Carolina, South Carolina, and Utah). The analytic cohort included 221 males with definite or probable DMD diagnosis without a documented family history. We computed frequency count and percentage for categorical variables, and mean, median, and standard deviation (SD) for continuous variables. RESULTS: The mean [median] ages in years of diagnostic milestones were: first signs, 2.7 [2.0]; first creatine kinase (CK), 4.6 [4.6]; DNA/muscle biopsy testing, 4.9 [4.8]; and time from first signs to diagnostic confirmation, 2.2 [1.4]. DISCUSSION: The time interval between first signs of DMD and diagnosis remains unchanged at 2.2 years. This results in lost opportunities for timely genetic counseling, implementation of standards of care, initiation of glucocorticoids, and participation in clinical trials.

Exome sequencing identifies variants in infants with sacral agenesis.

BACKGROUND: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA. METHODS: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced. RESULTS: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N = 1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N = 2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children. CONCLUSIONS: To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies.

Evaluation of effects of continued corticosteroid treatment on cardiac and pulmonary function in non-ambulatory males with Duchenne muscular dystrophy from MD STARnet.

INTRODUCTION/AIMS: Corticosteroids have been shown to improve muscle strength and delay loss of ambulation (LOA) in Duchenne muscular dystrophy (DMD) and are considered standard of care despite significant side-effects. The objective of this study is to evaluate whether corticosteroid treatment after LOA is beneficial for cardiac or pulmonary functions among boys with DMD. METHODS: We used the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) to characterize associations between corticosteroid use and onset of abnormal left ventricular (LV) function or abnormal percent predicted forced vital capacity (ppFVC) among 398 non-ambulatory boys with DMD. Kaplan-Meier curve estimation was used to compare time to onset by corticosteroid use groups; Cox proportional hazards modeling was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals. RESULTS: We found no differences in time to onset of abnormal LV function by corticosteroid use groups. We observed a longer time from LOA to first abnormal ppFVC in boys that were treated with corticosteroid ≥1 y beyond LOA compared with those with no corticosteroid use or those who stopped corticosteroid use within 1 y of LOA. DISCUSSION: Our findings show no association of corticosteroid use beyond LOA with the onset of abnormal LV function, but a significant association with a delay in onset of abnormal ppFVC. Prospective studies of corticosteroid use in boys with DMD who have lost ambulation may identify benefits and can better elucidate risks, allowing for more effective counseling of patients on continuing treatment after LOA.

Direct costs of adhering to selected Duchenne muscular dystrophy Care Considerations: Estimates from a midwestern state.

INTRODUCTION/AIMS: The multidisciplinary Duchenne muscular dystrophy (DMD) Care Considerations were developed to standardize care and improve outcomes. We provide cumulative cost estimates for selected key preventive (ie, excluding new molecular therapies and acute care) elements of the care considerations in eight domains (neuromuscular, rehabilitation, respiratory, cardiac, orthopedic, gastrointestinal, endocrine, psychosocial management) independent of completeness of uptake or provision of nonpreventive care. METHODS: We used de-identified insurance claims data from a large midwestern commercial health insurer during 2018. We used Current Procedural Terminology and national drug codes to extract unit costs for clinical encounters representing key preventive elements of the DMD Care Considerations. We projected per-patient cumulative costs from ages 5 to 25 years for these elements by multiplying a schedule of recommended frequencies of preventive services by unit costs in 2018 US dollars. RESULTS: Assuming a diagnosis at age 5 years, independent ambulation until age 11, and survival until age 25, we estimated 670 billable clinical events. The 20-year per-patient cumulative cost was $174 701 with prednisone ($2.3 million with deflazacort) and an expected total of $12 643 ($29 194) for out-of-pocket expenses associated with those events and medications. DISCUSSION: Standardized monitoring of disease progression and treatments may reduce overall costs of illness. Costs associated with these services would be needed to quantify potential savings. Our approach demonstrates a method to estimate costs associated with implementation of preventive care schedules.

Differentiation of Pediatric-Onset Duchenne and Becker Muscular Dystrophy Subphenotypes Using Data from the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet).

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) phenotypes are used to describe disease progression in affected individuals. However, considerable heterogeneity has been observed across and within these two phenotypes, suggesting a spectrum of severity rather than distinct conditions. Characterizing the phenotypes and subphenotypes aids researchers in the design of clinical studies and clinicians in providing anticipatory guidance to affected individuals and their families. Using data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet), we used K-means cluster analysis to group phenotypically similar males with pediatric-onset dystrophinopathy. We identified four dystrophinopathy clusters: Classical BMD, Classical DMD, late ambulatory DMD, and severe DMD. The clusters that we identified align with both 'classical' and 'non-classical' dystrophinopathy described in the literature. Individuals with dystrophinopathies have heterogenous clinical presentations that cluster into phenotypically similar groups. Use of clinically-derived phenotyping may provide a clearer understanding of disease trajectories, reduce variability in study results, and prevent exclusion of certain cohorts from analysis. Findings from studying subphenotypes may ultimately improve our ability to predict disease progression.

A population-based study of scoliosis among males diagnosed with a dystrophinopathy identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet).

INTRODUCTION/AIMS: Scoliosis is a common comorbidity among individuals diagnosed with a dystrophinopathy. We examined associations between clinical predictors and scoliosis in childhood-onset dystrophinopathy. METHODS: The progression and treatment of scoliosis were obtained from data collected by the US population-based Muscular Dystrophy Surveillance, Tracking, and Research Network. Associations between loss of independent ambulation (LoA) and corticosteroid use and scoliosis outcomes (ages at or exceeding Cobb angle thresholds [10°, 20°, 30°]; surgery) were estimated using Kaplan-Meier curve estimation and extended Cox regression modeling. RESULTS: We analyzed curvature data for 513 of 1054 individuals ascertained. Overall, approximately one-half had at least one radiograph and one-quarter had a curvature of at least 20°. The average maximum curvature was 25.0° (SD = 21.5°) among all individuals and 42.8° (SD = 18.8°) among those recommended for surgery. Higher adjusted hazards ratio of curvature (aHR(curvature) [95% confidence interval]) were found among individuals with LoA compared to those without LoA (aHR(10)  = 6.2 [4.4, 8.7], aHR(20)  = 15.3 [7.4, 31.7], aHR(30)  = 31.6 [7.7, 128.9]), among individuals who did not use corticosteroids compared to those who did (aHR(10)  = 1.2 [0.9, 1.7], aHR(20)  = 1.8 [1.1, 2.7], aHR(30)  = 2.3 [1.3, 4.0]), and among non-ambulatory individuals who used corticosteroids after LoA compared to those who did not (aHR(10)  = 1.8 [1.2, 2.8], aHR(20)  = 1.6 [1.0, 2.6], aHR(30)  = 3.6 [1.6, 7.9]). Scoliosis surgery among individuals with LoA who did not use corticosteroids was more than double compared to those who used (aHR = 2.3 [1.3, 4.2]). DISCUSSION: Our retrospective observational study suggests corticosteroids may delay spinal curvature progression and need for scoliosis surgery. Continuing corticosteroids after LoA also showed potential benefits of delaying curvature progression, additional studies are needed to confirm this finding or address the magnitude of benefit.

Characteristics of Clinical Trial Participants with Duchenne Muscular Dystrophy: Data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet).

BACKGROUND: Therapeutic trials are critical to improving outcomes for individuals diagnosed with Duchenne muscular dystrophy (DMD). Understanding predictors of clinical trial participation could maximize enrollment. METHODS: Data from six sites (Colorado, Iowa, Piedmont region North Carolina, South Carolina, Utah, and western New York) of the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) were analyzed. Clinical trial participation and individual-level clinical and sociodemographic characteristics were obtained from medical records for the 2000-2015 calendar years. County-level characteristics were determined from linkage of the most recent county of residence identified from medical records and publicly available federal datasets. Fisher's exact and Wilcoxon two-sample tests were used with statistical significance set at one-sided p-value (<0.05) based on the hypothesis that nonparticipants had fewer resources. RESULTS: Clinical trial participation was identified among 17.9% (MD STARnet site: 3.7-27.3%) of 358 individuals with DMD. Corticosteroids, tadalafil, and ataluren (PTC124) were the most common trial medications recorded. Fewer non-Hispanic blacks or Hispanics than non-Hispanic whites participated in clinical trials. Trial participants tended to reside in counties with lower percentages of non-Hispanic blacks. Conclusion: Understanding characteristics associated with clinical trial participation is critical for identifying participation barriers and generalizability of trial results. MD STARnet is uniquely able to track clinical trial participation through surveillance and describe patterns of participation.