Finding the Right Distribution for Highly Skewed Zero-inflated Clinical Data

Discrete, highly skewed distributions with excess numbers of zeros often result in biased estimates and misleading inferences if the zeros are not properly addressed. A clinical example of children with electrophysiologic disorders in which many of the children are treated without surgery is provided. The purpose of the current study was to identify the optimal modeling strategy for highly skewed, zeroinflated data often observed in the clinical setting by: (a) simulating skewed, zero-inflated count data; (b) fitting simulated data with Poisson, Negative Binomial, Zero-Inflated Poisson (ZIP) and Zero-inflated Negative Binomial (ZINB) models; and, (c) applying the aforementioned models to actual, highlyskewed, clinical data of children with an EP disorder. The ZIP model was observed to be the optimal model based on traditional fit statistics as well as estimates of bias, mean-squared error, and coverage. &nbsp

The Role of Abnormal Placentation in Congenital Heart Disease; Cause, Correlate, or Consequence?

Congenital heart disease (CHD) is the most common birth defect, affecting ~1% of all live births (van der Linde et al., 2011). Despite improvements in clinical care, it is the leading cause of infant mortality related to birth defects (Yang et al., 2006) and burdens survivors with significant morbidity (Gilboa et al., 2016). Furthermore, CHD accounts for the largest proportion (26.7%) of birth defect-associated hospitalization costs—up to $6.1 billion in 2013 (Arth et al., 2017). Yet after decades of research with a primary focus on genetic etiology, the underlying cause of these defects remains unknown in the majority of cases (Zaidi and Brueckner, 2017). Unexplained CHD may be secondary to undiscovered roles of noncoding genetic, epigenetic, and environmental factors, among others (Russell et al., 2018). Population studies have recently demonstrated that pregnancies complicated by CHD also carry a higher risk of developing pathologies associated with an abnormal placenta including growth disturbances (Puri et al., 2017), preeclampsia (Auger et al., 2015; Brodwall et al., 2016), preterm birth (Laas et al., 2012), and stillbirth (Jorgensen et al., 2014). Both the heart and placenta are vascular organs and develop concurrently; therefore, shared pathways almost certainly direct the development of both. The involvement of placental abnormalities in congenital heart disease, whether causal, commensurate or reactive, is under investigated and given the common developmental window and shared developmental pathways of the heart and placenta and concurrent vasculature development, we propose that further investigation combining clinical data, in vitro, in vivo, and computer modeling is fundamental to our understanding and the potential to develop therapeutics

Comparison of Magnetic Resonance Feature Tracking for Strain Calculation With Harmonic Phase Imaging Analysis

ObjectivesTo compare a steady-state free precession cine sequence–based technique (feature tracking [FT]) to tagged harmonic phase (HARP) analysis for peak average circumferential myocardial strain (εcc) analysis in a large and heterogeneous population of boys with Duchenne muscular dystrophy (DMD).BackgroundCurrent εcc assessment techniques require cardiac magnetic resonance–tagged imaging sequences, and their analysis is complex. The FT method can readily be performed on standard cine (steady-state free precession) sequences.MethodsWe compared mid-left ventricular whole-slice εcc by the 2 techniques in 191 DMD patients grouped according to age and severity of cardiac dysfunction: group B: DMD patients 10 years and younger with normal ejection fraction (EF); group C: DMD patients older than 10 years with normal EF; group D: DMD patients older than 10 years with reduced EF but negative myocardial delayed enhancement (MDE); group E: DMD patients older than 10 years with reduced EF and positive MDE; and group A: 42 control subjects. Retrospective, offline analysis was performed on matched tagged and steady-state free precession slices.ResultsFor the entire study population (N = 233), mean FT εcc values (−13.3 ± 3.8%) were highly correlated with HARP εcc values (−13.6 ± 3.4%), with a Pearson correlation coefficient of 0.899. The mean εcc of DMD patients determined by HARP (−12.52 ± 2.69%) and FT (−12.16 ± 3.12%) was not significantly different (p = NS). Similarly, the mean εcc of the control subjects by determined HARP (−18.85 ± 1.86) and FT (−18.81 ± 1.83) was not significantly different (p = NS). Excellent correlation between the 2 methods was found among subgroups A through E, except there was no significant difference in strain between groups B and C with FT analysis.ConclusionsFT-based assessment of εcc correlates highly with εcc derived from tagged images in a large DMD patient population with a wide range of cardiac dysfunction and can be performed without additional imaging

Six-Year Neurodevelopmental Outcomes for Children With Single-Ventricle Physiology

OBJECTIVES: To determine if neurodevelopmental deficits in children with single-ventricle physiology change with age and early developmental scores predict 6-year outcomes. METHODS: In the Single Ventricle Reconstruction Trial, Bayley Scales of Infant Development, Second Edition, were administered at 14 months of age, and parents completed the Behavior Assessment System for Children, Second Edition (BASC-2) annually from the ages of 2 to 6 years. Scores were classified as average, at risk, or impaired. We calculated sensitivities, specificities, and positive and negative predictive values of earlier tests on 6-year outcomes. RESULTS: Of 291 eligible participants, 244 (84%) completed the BASC-2 at 6 years; more Single Ventricle Reconstruction participants than expected on the basis of normative data scored at risk or impaired on the BASC-2 Adaptive Skills Index at that evaluation (28.7% vs 15.9%; P < .001). Children with Adaptive Skills Composite scores <2 SD below the mean at the age of 6 were more likely to have had delayed development at 14 months, particularly on the Psychomotor Development Index (sensitivity of 79%). However, the positive predictive value of the 14-month Mental Development Index and Psychomotor Development Index for 6-year BASC-2 Adaptive Scores was low (44% and 36%, respectively). Adaptive Skills Composite score impairments at the age of 6 were poorly predicted by using earlier BASC-2 assessments, with low sensitivities at the ages of 3 (37%), 4 (48%), and 5 years (55%). CONCLUSIONS: Many children with hypoplastic left heart syndrome who have low adaptive skills at the age of 6 years will not be identified by screening at earlier ages. With our findings, we highlight the importance of serial evaluations for children with critical congenital heart disease throughout development

Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study

Background: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. Methods: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. Results: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. Conclusions: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD