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Importance: The genetic factors that modulate the reduced penetrance and variable expressivity of heritable dilated cardiomyopathy (DCM) are largely unknown. BAG3 genetic variants have been implicated in both DCM and hypertrophic cardiomyopathy (HCM), nominating BAG3 as a gene that harbors potential modifier variants in DCM., Objective: To interrogate the clinical traits and diseases associated with BAG3 coding variation., Design, Setting, and Participants: This was a cross-sectional study in the Penn Medicine BioBank (PMBB) enrolling patients of the University of Pennsylvania Health System's clinical practice sites from 2014 to 2023. Whole-exome sequencing (WES) was linked to electronic health record (EHR) data to associate BAG3 coding variants with EHR phenotypes. This was a health care population-based study including individuals of European and African genetic ancestry in the PMBB with WES linked to EHR phenotypes, with replication studies in BioVU, UK Biobank, MyCode, and DCM Precision Medicine Study., Exposures: Carrier status for BAG3 coding variants., Main Outcomes and Measures: Association of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes., Results: In PMBB (n = 43 731; median [IQR] age, 65 [50-76] years; 21 907 female [50.1%]), among 30 324 European and 11 198 African individuals, the common C151R variant was associated with decreased risk for DCM (odds ratio [OR], 0.85; 95% CI, 0.78-0.92) and simultaneous increased risk for HCM (OR, 1.59; 95% CI, 1.25-2.02), which was confirmed in the replication cohorts. C151R carriers exhibited improved longitudinal outcomes compared with noncarriers as assessed by age at death (hazard ratio [HR], 0.85; 95% CI, 0.74-0.96; median [IQR] age, 71.8 [63.1-80.7] in carriers and 70.3 [61.6-79.2] in noncarriers) and heart transplant (HR, 0.81; 95% CI, 0.66-0.99; median [IQR] age, 56.7 [46.1-63.1] in carriers and 55.6 [45.2-62.9] in noncarriers). C151R was associated with reduced risk of DCM (OR, 0.42; 95% CI, 0.24-0.74) and heart failure (OR, 0.27; 95% CI, 0.14-0.50) among individuals harboring truncating TTN variants in exons with high cardiac expression (n = 358)., Conclusions and Relevance: BAG3 C151R was identified as a bidirectional modulator of risk along the DCM-HCM spectrum, as well as an important genetic modifier variant in TTN-mediated DCM. This work expands on the understanding of the etiology and penetrance of DCM, suggesting that BAG3 C151R is an important genetic modifier variant contributing to the variable expressivity of DCM, warranting further exploration of its mechanisms and of genetic modifiers in DCM more broadly.

Background: Clinical genetic evaluation of dilated cardiomyopathy (DCM) is implemented variably or not at all. Identifying needs and barriers to genetic evaluations will enable strategies to enhance precision medicine care., Methods: An online survey was conducted in June 2024 among cardiologist investigators of the DCM Consortium from US advanced heart failure/transplant (HF/TX) programs to collect demographics, training, program characteristics, genetic evaluation practices for DCM, and implementation needs. An in-person discussion followed., Results: Twenty-five cardiologists (28% female, 12% Hispanic, 68% White) participated in the survey and 15 in the discussion; genetics training backgrounds varied greatly. Clinical genetic testing for DCM was conducted by all programs with annual uptake ranging from 5%-70% (median 25%). Thirteen respondents (52%) did not use selection criteria for testing whereas others selected patients based on specific clinical and family history data. Eight (32%) ordered testing by themselves, and the remainder had testing managed mostly by a genetic counselor or others with genetic expertise (16/17; 94%). Six themes were distilled from open-ended responses regarding thoughts for the future and included access to genetics services, navigating uncertainty, knowledge needs, cost concerns, family-based care barriers, and institutional infrastructure limitations. Following an in-person discussion, four areas were identified for focused effort: improved reimbursement for genetic services, genetic counselor integration with HF/TX teams, improved provider education resources, and more research to find missing heritability and to resolve uncertain results., Conclusions: HF/TX programs have implementation challenges in the provision of DCM genetic evaluations; targeted plans to facilitate precision medicine for DCM are needed.

Background: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied., Methods: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link., Results: Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD., Conclusions: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03037632., Competing Interests: Disclosures None.

Importance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients., Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM., Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance., Exposure: Presence of DCM., Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic)., Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001)., Conclusion and Relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

Background: Cardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD)., Objectives: This study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients., Methods: Adult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results., Results: A total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM., Conclusions: Cardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs., Competing Interests: Funding Support and Author Disclosures Research reported in this publication was supported by a parent award from the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number R01HL128857, which included a supplement from the National Human Genome Research Institute. The DCM Precision Medicine Study was supported by computational infrastructure provided by The Ohio State University Division of Human Genetics Data Management Platform and the Ohio Supercomputer Center. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive., Methods: The DCM Precision Medicine Study developed Family Heart Talk , a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband., Results: Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive Family Heart Talk (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the Family Heart Talk arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the Family Heart Talk arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08-∞]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata ( P =0.90)., Conclusions: Family Heart Talk , a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of these patients., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03037632.

Importance: Cardiovascular disease contributes outsized mortality in patients from underrepresented racial and ethnic groups. Understanding levels of trust in medical researchers and knowledge of genome sequencing may help identify barriers to research participation and develop strategies to educate patients about the role of genetics in cardiovascular disease., Objective: To assess racial and ethnic differences in trust in medical researchers and genome-sequencing knowledge among patients with idiopathic dilated cardiomyopathy and determine the association between trust in medical researchers and genome-sequencing knowledge., Design, Setting, and Participants: This cross-sectional study conducted by a consortium of 25 US heart failure programs included patients with idiopathic dilated cardiomyopathy defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes. Enrollment occurred from June 7, 2016, to March 15, 2020., Main Outcomes and Measures: Percent distributions, means, and associations of genome-sequencing knowledge scores and research trust scores for Hispanic, non-Hispanic Black (hereafter referred to as Black), and non-Hispanic White participants (hereafter referred to as White)., Results: Among 1121 participants, mean (SD) age was 51.6 (13.6) years with 41.4% Black, 8.5% Hispanic, and 43.4% female. After accounting for site effects, the level of genome-sequencing knowledge was lower in Hispanic and Black participants compared with White participants (mean score difference, -2.6; 95% CI, -3.9 to -1.2 and mean score difference, -2.9; 95% CI, -3.6 to -2.2, respectively). The level of trust in researchers was lowest in Black participants (mean score, 27.7), followed by Hispanic participants (mean score, 29.4) and White participants (mean score, 33.9). Racial and ethnic differences remained after adjusting for education, age at enrollment, duration of dilated cardiomyopathy, and health status. A higher level of trust was associated with a higher level of genome-sequencing knowledge within different racial and ethnic groups., Conclusions and Relevance: In this cross-sectional study, large racial and ethnic differences in levels of genome-sequencing knowledge and trust in medical researchers were observed among patients with dilated cardiomyopathy. Findings from this study can inform future studies that aim to enhance the uptake of genomic knowledge and level of trust in medical researchers.

Purpose: The cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported., Methods: Exome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes., Results: Rare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99)., Conclusion: Among the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Assuring that relatives are informed about a genetic diagnosis and have appropriate medical follow-up can be challenging. We hypothesize that communal coping (CC)-an approach in which a group views a stressor (such as a new genetic diagnosis) as our problem, versus my or your problem, and takes joint action to address it-can help families to address this challenge. A better understanding of CC could also inform counseling interventions to promote CC and family follow-up., Methods: In the Dilated Cardiomyopathy (DCM) PM study (Precision Medicine), living first-degree relatives of DCM probands were invited to undergo clinical screening; 31% of these did so. This research program offers the opportunity to determine the frequency of CC in DCM families, assess whether CC attitudes and actions occurred more commonly among families in which family members participated, and conduct prospective follow-up to evaluate family coping and counseling needs over time., Results: The proposed studies will provide evidence about the frequency of CC attitudes and actions among DCM families, assess the association of CC with increased family follow-up, and identify counseling needs related to family follow-up., Conclusions: The DCM PM study offers an opportunity to test the hypothesis that CC contributes to increased family follow-up and generate evidence to inform counseling interventions to encourage such follow-up.

Importance: Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death., Objective: To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups., Design, Setting, and Participants: A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively., Exposures: The presence of DCM in a proband., Main Outcomes and Measures: Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative., Results: The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83])., Conclusions and Relevance: In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives., Trial Registration: ClinicalTrials.gov Identifier: NCT03037632.

Our insight into the diverse and complex nature of dilated cardiomyopathy (DCM) genetic architecture continues to evolve rapidly. The foundations of DCM genetics rest on marked locus and allelic heterogeneity. While DCM exhibits a Mendelian, monogenic architecture in some families, preliminary data from our studies and others suggests that at least 20% to 30% of DCM may have an oligogenic basis, meaning that multiple rare variants from different, unlinked loci, determine the DCM phenotype. It is also likely that low-frequency and common genetic variation contribute to DCM complexity, but neither has been examined within a rare variant context. Other types of genetic variation are also likely relevant for DCM, along with gene-by-environment interaction, now established for alcohol- and chemotherapy-related DCM. Collectively, this suggests that the genetic architecture of DCM is broader in scope and more complex than previously understood. All of this elevates the impact of DCM genetics research, as greater insight into the causes of DCM can lead to interventions to mitigate or even prevent it and thus avoid the morbid and mortal scourge of human heart failure.

Precision medicine genetics study design requires large, diverse cohorts and thoughtful use of electronic technologies. Involving patients in research design may increase enrollment and engagement, thereby enabling a means to relevant patient outcomes in clinical practice. Few data, however, illustrate attitudes of patients with dilated cardiomyopathy (DCM) and their family members toward genetic study design. This study assessed attitudes of 16 enrolled patients and their family members (P/FM), and 18 investigators or researchers (I/R) of the ongoing DCM Precision Medicine Study during a conjoint patient and investigator meeting using structured, self-administered surveys examining direct-to-participant enrollment and web-based consent, return of genetic results, and other aspects of genetic study design. Survey respondents were half women and largely identified as white. Web-based consent was supported by 93% of P/FM and 88% of I/R. Most respondents believed that return of genetic results would motivate study enrollment, but also indicated a desire to opt out. Ideal study design preferences included a 1-hour visit per year, along with the ability to complete study aspects by telephone or web and possibility of prophylactic medication. This study supports partnership of patients and clinical researchers to inform research priorities and study design to attain the promise of precision medicine for DCM., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disease characterized by progressive ventricular enlargement and reduced systolic function. Here, we report genetic and functional analyses implicating the rat sarcoma signaling protein, SOS1 (Son of sevenless homolog 1), in DCM pathogenesis., Methods: Exome sequencing was performed on 412 probands and family members from our DCM cohort, identifying several SOS1 variants with potential disease involvement. As several lines of evidence have implicated dysregulated rat sarcoma signaling in the pathogenesis of DCM, we assessed functional impact of each variant on the activation of ERK (extracellular signal-regulated kinase), AKT (protein kinase B), and JNK (c-Jun N-terminal kinase) pathways. Relative expression levels were determined by Western blot in HEK293T cells transfected with variant or wild-type human SOS1 expression constructs., Results: A rare SOS1 variant [c.571G>A, p.(Glu191Lys)] was found to segregate alongside an A-band TTN truncating variant in a pedigree with aggressive, early-onset DCM. Reduced disease severity in the absence of the SOS1 variant suggested its potential involvement as a genetic risk factor for DCM in this family. Exome sequencing identified 5 additional SOS1 variants with potential disease involvement in 4 other families [c.1820T>C, p.(Ile607Thr); c.2156G>C, p.(Gly719Ala); c.2230A>G, p.(Arg744Gly); c.2728G>C, p.(Asp910His); c.3601C>T, p.(Arg1201Trp)]. Impacted amino acids occupied a number of functional domains relevant to SOS1 activity, including the N-terminal histone fold, as well as the C-terminal REM (rat sarcoma exchange motif), CDC25 (cell division cycle 25), and PR (proline-rich) tail domains. Increased phosphorylated ERK expression relative to wild-type levels was seen for all 6 SOS1 variants, paralleling known disease-relevant SOS1 signaling profiles., Conclusions: These data support gain-of-function variation in SOS1 as a contributing factor to isolated DCM.

Background: The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen's MYH7 -cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy. To this end, we tailored the ClinGen MYH7 -cardiomyopathy variant interpretation framework; the specifications implemented for the study are presented here., Methods: Modifications were created and approved by an external Variant Adjudication Oversight Committee. After a pilot using 81 probands, further adjustments were made, resulting in 27 criteria (9 modifications of the ClinGen MYH7 framework and reintroduction of 2 American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria that were deemed not applicable by the ClinGen MYH7 working group)., Results: These criteria were applied to 2059 variants in a test set of 97 probands. Variants were classified as benign (n=1702), likely benign (n=33), uncertain significance (n=71), likely pathogenic (likely pathogenic; n=12), and pathogenic (P; n=3). Only 2/15 likely pathogenic/P variants were identified in Non-Hispanic African ancestry probands., Conclusions: We tailored the ClinGen MYH7 criteria for our study. Our preliminary data show that 15/97 (15.5%) probands have likely pathogenic/P variants, most of which were identified in probands of Non-Hispanic European ancestry. We anticipate continued evolution of our approach, one that will be informed by new insights on variant interpretation and a greater understanding of the genetic architecture of dilated cardiomyopathy., Clinical Trial Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.

Refined estimates of risk based on genetic risk modifiers could assist BRCA mutation carriers in understanding their risk, but it is not clear whether carriers are interested in receiving these estimates or how they might benefit from them. Using qualitative interviews, we investigated female BRCA 1 and BRCA 2 mutation carriers' (N = 20) reactions to numerical and verbal presentations of breast cancer risk based on risk modifiers and assessed women's preferences regarding visual formats for communicating risk. Our results show carriers are interested in receiving refined risk estimates and suggest the estimates may influence decision-making regarding cancer prevention, depending on the nature of the risk assessment. Although accurate and precise estimates of breast cancer risk are most important to women, they preferred quantitative risk estimates expressed as a proportion with or without a population comparison; however, women noted that comparisons to other BRCA mutation carriers were less useful given their high risk. Participants also preferred communication of a risk as a specific percentage versus a range of risk, but a clear preference regarding visual displays was not expressed. Results support many existing recommendations for genetic risk communication and provide guidance for the development of tools incorporating genetic risk modifiers.

Background: We have previously described 19 pedigrees with apparent lamin ( LMNA )-related dilated cardiomyopathy (DCM) manifesting in affected family members across multiple generations. In 6 of 19 families, at least 1 individual with idiopathic DCM did not carry the family's LMNA variant. We hypothesized that additional genetic cause may underlie DCM in these families., Methods: Affected family members underwent exome sequencing to identify additional genetic cause of DCM in the 6 families with nonsegregating LMNA variants., Results: In 5 of 6 pedigrees, we identified at least 1 additional rare variant in a known DCM gene that could plausibly contribute to disease in the LMNA variant-negative individuals. Bilineal inheritance was clear or presumed to be present in 3 of 5 families and was possible in the remaining 2. At least 1 individual with a LMNA variant also carried a variant in an additional identified DCM gene in each family. Using a multivariate linear mixed model for quantitative traits, we demonstrated that the presence of these additional variants was associated with a more severe phenotype after adjusting for sex, age, and the presence/absence of the family's nonsegregating LMNA variant., Conclusions: Our data support DCM as a genetically heterogeneous disease with, at times, multigene causation. Although the frequency of DCM resulting from multigenic cause is uncertain, our data suggest it may be higher than previously anticipated., (© 2018 American Heart Association, Inc.)

Background: The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality., Methods: On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity-ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk , an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives., Conclusions: We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03037632., (© 2017 American Heart Association, Inc.)

Family-based designs have been commonly used in association studies. Different family structures such as extended pedigrees and nuclear families, including parent-offspring triads and families with multiple affected siblings (multiplex families), can be ascertained for family-based association analysis. Flexible association tests that can accommodate different family structures have been proposed. The pedigree disequilibrium test (PDT) (Martin et al., Am J Hum Genet 67:146-154, 2000) can use full genotype information from general (possibly extended) pedigrees with one or multiple affected siblings but requires parental genotypes or genotypes of unaffected siblings. On the other hand, the association in the presence of linkage (APL) test (Martin et al., Am J Hum Genet 73:1016-1026, 2003) is restricted to nuclear families with one or more affected siblings but can infer missing parental genotypes properly by accounting for identity-by-descent (IBD) parameters. Both the PDT and APL test are powerful association tests in the presence of linkage and can be used as complementary tools for association analysis. This chapter introduces these two tests and compares their properties. Recommendations and notes for performing the tests in practice are provided.

Monte Carlo permutation tests can be formally constructed by choosing a set of permutations of individual indices and a real-valued test statistic measuring the association between genotypes and affection status. In this paper, we develop a rigorous theoretical framework for verifying the validity of these tests when there are missing genotypes. We begin by specifying a nonparametric probability model for the observed genotype data in a genetic case-control study with unrelated subjects. Under this model and some minimal assumptions about the test statistic, we establish that the resulting Monte Carlo permutation test is exact level α if (1) the chosen set of permutations of individual indices is a group under composition and (2) the distribution of the observed genotype score matrix under the null hypothesis does not change if the assignment of individuals to rows is shuffled according to an arbitrary permutation in this set. We apply these conditions to show that frequently used Monte Carlo permutation tests based on the set of all permutations of individual indices are guaranteed to be exact level α only for missing data processes satisfying a rather restrictive additional assumption. However, if the missing data process depends on covariates that are all identified and recorded, we also show that Monte Carlo permutation tests based on the set of permutations within strata of individuals with identical covariate values are exact level α. Our theoretical results are verified and supplemented by simulations for a variety of missing data processes and test statistics., (© 2014 WILEY PERIODICALS, INC.)

Objective: Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes., Methods: We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics., Results: We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD., Conclusions: We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.

Association tests that pool minor alleles into a measure of burden at a locus have been proposed for case-control studies using sequence data containing rare variants. However, such pooling tests are not robust to the inclusion of neutral and protective variants, which can mask the association signal from risk variants. Early studies proposing pooling tests dismissed methods for locus-wide inference using nonnegative single-variant test statistics based on unrealistic comparisons. However, such methods are robust to the inclusion of neutral and protective variants and therefore may be more useful than previously appreciated. In fact, some recently proposed methods derived within different frameworks are equivalent to performing inference on weighted sums of squared single-variant score statistics. In this study, we compared two existing methods for locus-wide inference using nonnegative single-variant test statistics to two widely cited pooling tests under more realistic conditions. We established analytic results for a simple model with one rare risk and one rare neutral variant, which demonstrated that pooling tests were less powerful than even Bonferroni-corrected single-variant tests in most realistic situations. We also performed simulations using variants with realistic minor allele frequency and linkage disequilibrium spectra, disease models with multiple rare risk variants and extensive neutral variation, and varying rates of missing genotypes. In all scenarios considered, existing methods using nonnegative single-variant test statistics had power comparable to or greater than two widely cited pooling tests. Moreover, in disease models with only rare risk variants, an existing method based on the maximum single-variant Cochran-Armitage trend chi-square statistic in the locus had power comparable to or greater than another existing method closely related to some recently proposed methods. We conclude that efficient locus-wide inference using single-variant test statistics should be reconsidered as a useful framework for devising powerful association tests in sequence data with rare variants.

Motivation: Next-generation sequencing presents several statistical challenges, with one of the most fundamental being determining an individual's genotype from multiple aligned short read sequences at a position. Some simple approaches for genotype calling apply fixed filters, such as calling a heterozygote if more than a specified percentage of the reads have variant nucleotide calls. Other genotype-calling methods, such as MAQ and SOAPsnp, are implementations of Bayes classifiers in that they classify genotypes using posterior genotype probabilities., Results: Here, we propose a novel genotype-calling algorithm that, in contrast to the other methods, estimates parameters underlying the posterior probabilities in an adaptive way rather than arbitrarily specifying them a priori. The algorithm, which we call SeqEM, applies the well-known Expectation-Maximization algorithm to an appropriate likelihood for a sample of unrelated individuals with next-generation sequence data, leveraging information from the sample to estimate genotype probabilities and the nucleotide-read error rate. We demonstrate using analytic calculations and simulations that SeqEM results in genotype-call error rates as small as or smaller than filtering approaches and MAQ. We also apply SeqEM to exome sequence data in eight related individuals and compare the results to genotypes from an Illumina SNP array, showing that SeqEM behaves well in real data that deviates from idealized assumptions., Conclusion: SeqEM offers an improved, robust and flexible genotype-calling approach that can be widely applied in the next-generation sequencing studies., Availability and Implementation: Software for SeqEM is freely available from our website: www.hihg.org under Software Download.

The hydration of fat-free mass, or hydration fraction (HF), is often defined as a constant body composition parameter in a two-compartment model and then estimated from in vivo measurements. We showed that the widely used estimator for the HF parameter in this model, the mean of the ratios of measured total body water (TBW) to fat-free mass (FFM) in individual subjects, can be inaccurate in the presence of additive technical errors. We then proposed a new instrumental variables estimator that accurately estimates the HF parameter in the presence of such errors. In Monte Carlo simulations, the mean of the ratios of TBW to FFM was an inaccurate estimator of the HF parameter, and inferences based on it had actual type I error rates more than 13 times the nominal 0.05 level under certain conditions. The instrumental variables estimator was accurate and maintained an actual type I error rate close to the nominal level in all simulations. When estimating and performing inference on the HF parameter, the proposed instrumental variables estimator should yield accurate estimates and correct inferences in the presence of additive technical errors, but the mean of the ratios of TBW to FFM in individual subjects may not.

The feasibility and effectiveness of a hospital-based exercise-training program followed by a home-based program for improving fitness, strength, and changes in body composition in children and adolescents with HIV were evaluated. Subjects participated in nonrandomized 24-session, hospital supervised exercise training program followed by an 314 unsupervised home-based maintenance program. Outcome measurements included muscular strength/endurance, flexibility, relative peak VO(2), body composition, and lipids. Seventeen subjects (eight females) with a median age of 15.0 years (range: 6.0-22.6) and BMI z-score of 0.61 (range: -1.70-2.57) at entry completed the intervention. After 24 training sessions, the median increases in muscular strength were between 8% and 50%, depending on muscle group. The median increases in muscle endurance, relative peak VO(2), and lean body mass were 38.7% (95% CI: 12.5-94.7; p = 0.006), 3.0 ml/kg/min (95% CI: 1.5-6.0; p < 0.001), and 4.5% (95% CI: 2.4-6.6; p < 0.001), respectively. Twelve children completed the home-based maintenance program. Median changes in these outcomes between completion of the hospital-based intervention and a follow-up after completion of the home-based program were near zero. No adverse events occurred during the intervention. A supervised hospital-based fitness program is feasible, safe, and effective for improving general fitness and strength as well as lean body mass in children with HIV.

Rare mutations in more than 20 genes have been suggested to cause dilated cardiomyopathy (DCM), but explain only a small percentage of cases, mainly in familial forms. We hypothesised that more common variants may also play a role in increasing genetic susceptibility to DCM, similar to that observed in other common complex disorders. To test this hypothesis, we performed case-control analyses on all DNA polymorphic variation identified in a resequencing study of six candidate DCM genes (CSRP3, LDB3, MYH7, SCN5A, TCAP, and TNNT2) conducted in 289 unrelated white probands with DCM of unknown cause and 188 unrelated white controls. In univariate analyses, we identified associated common variants at LDB3 site 10779, LDB3 site 57877, MYH7 sites 16384 and 17404, and TCAP sites 140 and 1735. Multivariate analyses to examine the joint effects of multiple gene variants confirmed univariate results for MYH7 and TCAP and identified a block of nine variants in MYH7 that was strongly associated with DCM. Common variants in genes known to be causative of DCM may play a role in genetic susceptibility to DCM. Our results suggest that examination of common genetic variants may be warranted in future studies of DCM and other Mendelian-like disorders.

Background: Nutritional concerns in HIV-infected children have evolved, from wasting to obesity and insulin resistance. However, little is known about the diet of these children during this evolution., Objective: We analyzed dietary macronutrient intake in HIV-infected children over nearly 10 y., Design: HIV-infected children underwent periodic longitudinal nutritional assessments between 1995 and 2004. Sex-specific initial and final means or proportions and time trends in macronutrient intakes were estimated with regression analyses., Results: Three hundred thirty nutritional records from 49 males and 411 from 67 females were analyzed. Caloric intake exceeded the estimated energy requirement (EER) for ideal body weight in 1995 by 62% for males and 39% for females and decreased by 3% of the EER per year in males (P = 0.02) and by 2% in females (P = 0.004). In 2004, caloric intake still remained >19% above the EER in both groups. Protein intake was nearly 400% of the recommended dietary allowance (RDA) for ideal body weight in 1995 among both males and females and decreased by 13% of the RDA per year for males (P = 0.001) and by 21% per year for females (P < 0.001). However, daily protein intake still exceeded the RDA by >60% in both groups in 2004. Females consumed more energy from carbohydrates (P = 0.05) and sugar (P = 0.10) and less from monounsaturated (P = 0.04), polyunsaturated (P = 0.05), saturated (P = 0.03), and total (P = 0.10) fat in 2004 than in 1995., Conclusion: Excessive caloric intake and a shift in dietary composition toward carbohydrates in females suggest that continued monitoring of diet in HIV-infected children is important to avoid increased nutritional risk.

Background: Adult heart failure (HF) has been shown to be associated with neuroendocrine and inflammatory activation. We hypothesize that neuroendocrine and inflammatory activation also associate with symptom severity and echocardiographic measurements in pediatric HF., Methods: Nineteen children with HF were divided into 3 symptom severity groups. Measurements were made of left ventricular (LV) ejection fraction, LV shortening fraction (LVSF), LV shortening fraction Z score (LVSFz), and LV end-systolic (LVSDz) and diastolic diameter Z scores. Blood levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha, and soluble tumor necrosis factor receptor II were measured., Results: NT-proBNP and hsCRP were significantly elevated with more severe symptoms (P < or = .003) and discriminated between clinical severity groups (volume under the receiver operating characteristic surface = 0.58 and 0.62, P = .007 and P = .002, respectively). NT-proBNP was negatively associated with LV ejection fraction, LVSF, and LVSFz (P < or = .05) and positively associated with LVSDz (P < .001). High-sensitivity C-reactive protein was negatively associated with LVSF (P = .02) and positively associated with NT-proBNP (P = .03). Tumor necrosis factor alpha was negatively associated with LVSF and LVSFz (P < or = .03) and positively associated with LVSDz and NT-proBNP (P < or = .02). Soluble tumor necrosis factor receptor II was negatively associated with LVSFz (P = .03)., Conclusions: Neuroendocrine and inflammatory activation are associated with more severe symptoms and worse cardiac characteristics in pediatric HF. Blood levels of these biomarkers could be used to better assess the severity of HF in children.

Objective: To study the risk factors for the development of moyamoya syndrome after cranial irradiation for primary brain tumors in children., Methods: We reviewed neuroimaging studies and dosimetry data for 456 children who were treated with radiation for a primary brain tumor and who were prospectively evaluated with serial neuroimaging studies and neurologic evaluations. A total of 345 patients had both adequate neuroimaging and radiation dosimetry data for further analysis. We used survival analysis techniques to examine the relationship of clinically important variables as risk factors for the development of moyamoya over time., Results: Overall, 12 patients (3.5%) developed evidence of moyamoya. The onset of moyamoya was more rapid for patients with neurofibromatosis type 1 (NF1) (median of 38 vs 55 months) and for patients who received >5,000 cGy of radiation (median of 42 vs 67 months). In a multiple Cox proportional hazards regression analysis controlling for age at start of radiation, each 100-cGy increase in radiation dose increased the rate of moyamoya by 7% (hazard ratio [HR] = 1.07, 95% CI: 1.02 to 1.13, p = 0.01) and the presence of NF1 increased the rate of moyamoya threefold (HR = 3.07, 95% CI: 0.90 to 10.46, p = 0.07)., Conclusions: Moyamoya syndrome is a potentially serious complication of cranial irradiation in children, particularly for those patients with tumors in close proximity to the circle of Willis, such as optic pathway glioma. Patients who received higher doses of radiation to the circle of Willis and with neurofibromatosis type 1 have increased risk of the development of moyamoya syndrome.

Objectives: To examine small mandibular size and preference for a hand-to-chin posture as salient characteristics in infants with a history of an apparent life-threatening event (ALTE)., Study Design: This was a prospective case-control study of term infants, from birth to 6 months of age, admitted post-ALTE and matched 1:2 with healthy control infants (age within 2 weeks and weight within 0.5 kg). Infants with confirmed gastroesophageal reflux and congenital anomalies, including severe micrognathia, were excluded., Results: Infants with a history of an ALTE (n = 25) were matched to 47 healthy controls. Infants with a history of an ALTE had mandibular indices (larger index indicates a smaller mandible) that were 3.8 mm greater on the left side (95% CI: 2.0-5.6, P < .001) and 4.2 mm greater on the right side (95% CI: 2.7-5.6, P < .001) adjusting for length and non-white race. Controlling for matching and length, a 1-mm increase in the average mandibular index increased the odds of an ALTE by 62% (OR = 1.62, 95% CI: 1.22-2.44, P < .001)., Conclusions: Smaller mandibular size was associated with ALTE, suggesting airway obstruction as a potential cause of ALTE. The association of this characteristic with ALTE also offers the potential for prospective quantification of ALTE risk.

Objective: Antenatal hydronephrosis is diagnosed in 1% to 5% of all pregnancies; however, the antenatal and postnatal management of hydronephrosis varies widely. No previous studies define the risk of postnatal pathology in infants with antenatal hydronephrosis. Our objective was to review the current literature to determine whether the degree of antenatal hydronephrosis and related antenatal ultrasound findings are associated with postnatal outcome., Methods: We searched Medline (1966-2005), Embase (1991-2004), and the Cochrane Library databases for articles on antenatal hydronephrosis. We required studies to have subjects selected on the basis of documented measurements of antenatal hydronephrosis and followed to a postnatal diagnosis. We excluded case reports, review articles, and editorials. Two independent investigators extracted data., Results: We screened 1645 citations, of which 17 studies met inclusion criteria. We created a data set of 1308 subjects. The risk of any postnatal pathology per degree of antenatal hydronephrosis was 11.9% for mild, 45.1% for moderate, and 88.3% for severe. There was a significant increase in risk per increasing degree of hydronephrosis. The risk of vesicoureteral reflux was similar for all degrees of antenatal hydronephrosis., Conclusions: The findings of this meta-analysis can potentially be used for prenatal counseling and may alter current postnatal management of children with antenatal hydronephrosis. Overall, children with any degree of antenatal hydronephrosis are at greater risk of postnatal pathology as compared with the normal population. Moderate and severe antenatal hydronephrosis have a significant risk of postnatal pathology, indicating that comprehensive postnatal diagnostic management should be performed. Mild antenatal hydronephrosis may carry a risk for postnatal pathology, but additional prospective studies are needed to determine the optimal management of these children. A well-defined prospective analysis is needed to further define the risk of pathology and the appropriate management protocols.

Background: Newborn screening programs now identify children with >30 biochemical genetic disorders. False-positive identifications may increase as disorders are added to screening panels. Concerns arise regarding the potential impact on parental stress, family relationships, and perceptions of the child's health., Methods: Parents of 173 infants with false-positive screening results for a biochemical genetic disorder in the expanded newborn screening panel were compared with parents of 67 children with normal screening results. Parents completed an interview that elicited information about demographic features, child and parental health, and understanding of newborn screening. Parents also completed the parenting stress index., Results: Parents in the false-positive group attained higher total scores on the PSI than did parents in the normal-screened group, scoring higher on the parent-child dysfunction subscale and the difficult child subscale. Only approximately one third of parents in the false-positive group reported knowing the correct reason for repeat screening. Mothers who reported knowing the correct reason for their child's repeat screening test experienced less total stress than did mothers who were misinformed, were not informed, or did not remember., Conclusions: False-positive screening results may affect parental stress and the parent-child relationship. Improved communication with parents regarding the need for repeat screening tests may reduce the negative impact of false-positive results.

We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 x 10(9)/L (50,000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP.

Purpose: We assessed bladder growth and dynamics following complete primary repair of bladder exstrophy (CPRE) compared to the staged approach., Materials and Methods: We reviewed the records of 16 boys and 7 girls who underwent CPRE within 3 days of life from 1996 to 2004 and compared them to the records of 8 boys and 6 girls treated with a staged repair from 1979 to 1996. Screening methods included voiding cystourethrogram, radionuclide cystogram and urodynamic study. We estimated growth curves for bladder capacity following repair in each group, and compared percent predicted bladder capacity (PPBC), compliance and detrusor overactivity between the CPRE and staged repair groups following bladder neck reconstruction., Results: Bladder capacity in the staged repair group was 69.8 ml (95% CI 46.7-104.4) immediately after bladder neck reconstruction and increased by 15.0% per year thereafter (95% CI 6.2-24.5, p = 0.002). In the CPRE group bladder capacity was 29.0 ml (95% CI 21.3-39.5) initially and increased by 28.9% per year thereafter (95% CI 17.4-41.5, p <0.001). PPBC started at 45.6% (95% CI 35.7-55.5) and increased 1.2% per year (95% CI -1.1-3.5, p = 0.29) following repair for all genders and surgery groups. Compliance was 124.4% (95% CI 22.6-310.7, p = 0.01) greater in the CPRE group at all times following repair. Detrusor overactivity was present in 0 of 19 patients in the CPRE group and 6 of 13 (46%) in the staged group (exact p = 0.002)., Conclusions: Within the CPRE group bladder stability was universal, and sphincter electromyography was normal suggesting no neuromuscular compromise of the pelvic floor. At early followup, our results suggest that PPBC is equivalent irrespective of gender or management. Further objective evaluation is needed in both groups.

Unlabelled: Cerebellar hemorrhage (CBH) in premature infants is increasingly diagnosed secondary to improved neuroimaging techniques and survival of very small preterm infants. Information is limited, however, on the incidence, topography, and risk factors for CBH in the preterm infant., Objectives: To define the incidence of CBH in preterm infants diagnosed by neonatal cranial ultrasound (US), describe the sonographic features of CBH, and identify maternal and perinatal risk factors associated with this lesion., Methods: A systematic electronic database search identified preterm infants born 1998-2002 with US diagnosis of CBH. For 35 cases of CBH we double-matched (according to gestational age, gender, and year of birth) 70 preterm controls with normal cranial USs and performed detailed medical-record reviews for both patients and controls., Results: Unilateral CBH was seen in 25 patients (71%), vermian hemorrhage was seen in 7 (20%), and combined bihemispheric and vermian hemorrhage was seen in 3 (9%). Isolated CBH occurred in 8 patients (23%); the remaining infants had associated supratentorial lesions. The incidence of CBH in preterm infants weighing <750 g at birth showed significant increase over the study period. Univariate analyses identified maternal, intrapartum, and early postnatal hemodynamic risk factors; multivariate regressions indicated that emergent caesarian section, patent ductus arteriosus, and lower 5-day minimum pH independently increased the odds of CBH. Neonatal mortality and morbidity were significantly higher among patients with CBH compared with preterm controls., Conclusions: CBH is an important complication of extreme preterm birth and has been underrecognized in surviving preterm infants. Predictors of CBH seem to be multifactorial and include combined maternal, intrapartum, and early postnatal factors.