Real World Data are Not Always Big Data: The Case for Primary Data Collection on Medication Use in Pregnancy in the Context of Birth Defects Research.

Many examples of the use of real-world data in the area of pharmacoepidemiology include "big data" such as insurance claims, medical records, or hospital discharge databases. However, "big" is not always better, particularly when studying outcomes with narrow windows of etiologic relevance. Birth defects are one such outcome, where specificity of exposure timing is critical. Studies with primary data collection can be designed to query details on the timing of medication use, as well as type, dose, frequency, duration, and indication, that can better characterize the "real world". Because birth defects are rare, etiologic studies are typically case-control in design, like the National Birth Defects Prevention Study, Birth Defects Study to Evaluate Pregnancy exposureS, and Slone Birth Defects Study. Recall bias can be a concern, but the ability to collect detailed information on both prescription and over-the-counter medication use and on other exposures such as diet, family history, and sociodemographic factors is a distinct advantage over claims and medical record data sources. Case-control studies with primary data collection are essential to advancing the pharmacoepidemiology of birth defects.

Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach.

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.

Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants.

The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.

Insights From the Transition to Competency-Based Medical Education in Neurology Programs.

Canadian neurology residency programs recently transitioned to Competency-Based Medical Education (CBME). Iterative evaluation is required to optimize CBME implementation. This study aimed to examine the variability and challenges in uptake of CBME in neurology residency programs and identify its benefits and pitfalls. Neurology residents and faculty participated in respective anonymous surveys. Common barriers to uptake were identified from both perspectives. Orientation to CBME was adequate, but workload was increased and contributed to burnout for faculty and residents. It is premature to draw conclusions regarding benefits of CBME. Future research considerations include standardization of entrustment scales and reduction of stakeholder burden.

A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study.

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (Ndiscovery  = 3978; Nreplication  = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (Ndiscovery_TDT  = 440; Nreplication_TDT  = 275) and case-control analyses separately in infants (Ndiscovery_CCI  = 1635; Nreplication_CCI  = 990) and mothers (case status defined by infant; Ndiscovery_CCM  = 1703; Nreplication_CCM  = 1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (pdiscovery  = 4.08 × 10-9 ; preplication  = 2.44 × 10-4 ). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (pdiscovery  = 1.61 × 10-7 ; preplication  = 0.0016). Two other SNPs were suggestively associated (p < 1 × 10-6 ) with OHD in only the discovery sample. In the case-control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds ( × discovery < 1 × 10-5 and preplication < 0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (pdiscovery  = 1.42 × 10-6 ; preplication  = 0.04). Additional SNPs with pdiscovery < 1 × 10-5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings.

Exome sequencing identifies genetic variants in anophthalmia and microphthalmia.

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

Using Deep Learning for Task and Tremor Type Classification in People with Parkinson's Disease.

Hand tremor is one of the dominating symptoms of Parkinson's disease (PD), which significantly limits activities of daily living. Along with medications, wearable devices have been proposed to suppress tremor. However, suppressing tremor without interfering with voluntary motion remains challenging and improvements are needed. The main goal of this work was to design algorithms for the automatic identification of the tremor type and voluntary motions, using only surface electromyography (sEMG) data. Towards this goal, a bidirectional long short-term memory (BiLSTM) algorithm was implemented that uses sEMG data to identify the motion and tremor type of people living with PD when performing a task. Moreover, in order to automate the training process, hyperparamter selection was performed using a regularized evolutionary algorithm. The results show that the accuracy of task classification among 15 people living with PD was 84±8%, and the accuracy of tremor classification was 88±5%. Both models performed significantly above chance levels (20% and 33% for task and tremor classification, respectively). Thus, it was concluded that the trained models, based on using purely sEMG signals, could successfully identify the task and tremor types.

Exome sequencing of child-parent trios with bladder exstrophy: Findings in 26 children.

Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency ≤ 0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.

Age Differences and Similarities in Associated Stressors and Outcomes Among Young, Midlife, and Older Adult Family Caregivers.

BACKGROUND AND OBJECTIVES: Few studies have simultaneously compared caregivers in all stages of the adult life course. This study examined age differences in associations among primary stressors (caregiver burden which includes hours of provided care and number of activities of daily living and instrumental activities of daily living performed), secondary stressors (financial and employment strains), and caregiver outcomes (emotional strain and physical strain). RESEARCH DESIGN: Using Pearlin's Stress Process Model (1990) and the Caregiving in the United States 2015 dataset, 1,156 caregivers were identified (including 278 young adults aged 18-39 years, 464 midlife adults aged 40-59 years, and 414 older adults aged 60-80 years). RESULTS: Post hoc analyses revealed that compared to older adults, young adults reported less caregiver burden, less physical strain, and greater financial strain. Linear regression analyses revealed associations between caregiver burden and financial strain with emotional and physical strain for all respondents. DISCUSSION AND IMPLICATIONS: Findings emphasize the need for age-specific interventions.

A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis.

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P = 4.71 × 10-9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10-8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10-9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10-8, OR = 0.45; P = 3.31 × 10-8, OR = 0.45; P = 1.09 × 10-8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10-8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10-6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

Dorsal striatum does not mediate feedback-based, stimulus-response learning: An event-related fMRI study in patients with Parkinson's disease tested on and off dopaminergic therapy.

Learning associations between stimuli and responses is essential to everyday life. Dorsal striatum (DS) has long been implicated in stimulus-response learning, though recent results challenge this contention. We have proposed that discrepant findings arise because stimulus-response learning methodology generally confounds learning and response selection processes. In 19 patients with Parkinson's disease (PD) and 18 age-matched controls, we found that dopaminergic therapy decreased the efficiency of stimulus-response learning, with corresponding attenuation of ventral striatum (VS) activation. In contrast, exogenous dopamine improved response selection accuracy related to enhanced DS BOLD signal. Contrasts between PD patients and controls fully support these within-subject patterns. These double dissociations in terms of behaviour and neural activity related to VS and DS in PD and in response to dopaminergic therapy, strongly refute the view that DS mediates stimulus-response learning through feedback. Our findings integrate with a growing literature favouring a role for DS in decision making rather than learning, and unite two literature that have been evolving independently.

Fire behavior and smoke modeling: Model improvement and measurement needs for next-generation smoke research and forecasting systems.

There is an urgent need for next-generation smoke research and forecasting (SRF) systems to meet the challenges of the growing air quality, health, and safety concerns associated with wildland fire emissions. This review paper presents simulations and experiments of hypothetical prescribed burns with a suite of selected fire behavior and smoke models and identifies major issues for model improvement and the most critical observational needs. The results are used to understand the new and improved capability required for the next-generation SRF systems and to support the design of the Fire and Smoke Model Evaluation Experiment (FASMEE) and other field campaigns. The next-generation SRF systems should have more coupling of fire, smoke, and atmospheric processes to better simulate and forecast vertical smoke distributions and multiple sub-plumes, dynamical and high-resolution fire processes, and local and regional smoke chemistry during day and night. The development of the coupling capability requires comprehensive and spatially and temporally integrated measurements across the various disciplines to characterize flame and energy structure (e.g., individual cells, vertical heat profile and the height of well mixing flaming gases), smoke structure (vertical distributions and multiple sub-plumes), ambient air processes (smoke eddy, entrainment and radiative effects of smoke aerosols), fire emissions (for different fuel types and combustion conditions from flaming to residual smoldering), as well as night-time processes (smoke drainage and super-fog formation).

Impact of sample collection participation on the validity of estimated measures of association in the National Birth Defects Prevention Study when assessing gene-environment interactions.

To better understand the impact that nonresponse for specimen collection has on the validity of estimates of association, we examined associations between self-reported maternal periconceptional smoking, folic acid use, or pregestational diabetes mellitus and six birth defects among families who did and did not submit buccal cell samples for DNA following a telephone interview as part of the National Birth Defects Prevention Study (NBDPS). Analyses included control families with live born infants who had no birth defects (N = 9,465), families of infants with anorectal atresia or stenosis (N = 873), limb reduction defects (N = 1,037), gastroschisis (N = 1,090), neural tube defects (N = 1,764), orofacial clefts (N = 3,836), or septal heart defects (N = 4,157). Estimated dates of delivery were between 1997 and 2009. For each exposure and birth defect, odds ratios and 95% confidence intervals were calculated using logistic regression stratified by race-ethnicity and sample collection status. Tests for interaction were applied to identify potential differences between estimated measures of association based on sample collection status. Significant differences in estimated measures of association were observed in only four of 48 analyses with sufficient sample sizes. Despite lower than desired participation rates in buccal cell sample collection, this validation provides some reassurance that the estimates obtained for sample collectors and noncollectors are comparable. These findings support the validity of observed associations in gene-environment interaction studies for the selected exposures and birth defects among NBDPS participants who submitted DNA samples.

Palliative Care Discussions in Multiple System Atrophy: A Retrospective Review.

OBJECTIVE: Multiple system atrophy (MSA) is an incurable neurodegenerative illness in which progressive symptoms, including stridor and acute laryngeal obstruction, occur. Advanced care planning and palliative care discussions in people living with MSA are not well defined. The aim of the present study is to evaluate advanced care planning and current practices in palliative care in MSA to identify opportunities for improving quality of care. METHODS: The study is a retrospective chart review assessing the focus and timing of palliative care discussions in people living with MSA. Some 22 charts were reviewed. RESULTS: A total of 22 patients were included. The most common symptoms were parkinsonism, orthostatic hypotension, GI/GU dysfunction, ataxia and gait impairment. Six patients had stridor. Of the palliative care discussions that took place, the most common topics were diagnosis, symptoms or symptom management, and prognosis. In the majority of patients who died and who had a do-not-attempt-resuscitation order, discussions surrounding resuscitation and goals of care took place only hours before death. CONCLUSIONS: There is no standard approach to advanced care planning and palliative care discussions in people living with MSA. We propose a framework to guide advanced care planning and palliative care discussions in MSA.

The National Birth Defects Prevention Study: A review of the methods.

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case-control study of major birth defects in the United States. METHODS: Data collection took place from 1998 through 2013 on pregnancies ending between October 1997 and December 2011. Cases could be live born, stillborn, or induced terminations, and were identified from birth defects surveillance programs in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Controls were live born infants without major birth defects identified from the same geographical regions and time periods as cases by means of either vital records or birth hospitals. Computer-assisted telephone interviews were completed with women between 6 weeks and 24 months after the estimated date of delivery. After completion of interviews, families received buccal cell collection kits for the mother, father, and infant (if living). RESULTS: There were 47,832 eligible cases and 18,272 eligible controls. Among these, 32,187 (67%) and 11,814 (65%), respectively, provided interview information about their pregnancies. Buccal cell collection kits with a cytobrush for at least one family member were returned by 19,065 case and 6,211 control families (65% and 59% of those who were sent a kit). More than 500 projects have been proposed by the collaborators and over 200 manuscripts published using data from the NBDPS through December 2014. CONCLUSION: The NBDPS has made substantial contributions to the field of birth defects epidemiology through its rigorous design, including case classification, detailed questionnaire and specimen collection, large study population, and collaborative activities across Centers.

Maternal smoking, xenobiotic metabolizing enzyme gene variants, and gastroschisis risk.

Maternal smoking during pregnancy is one proposed risk factor for gastroschisis, but reported associations have been modest, suggesting that differences in genetic susceptibility might play a role. We included 108 non-Hispanic white and 62 Hispanic families who had infants with gastroschisis, and 1,147 non-Hispanic white and 337 Hispanic families who had liveborn infants with no major structural birth defects (controls) in these analyses. DNA was extracted from buccal cells collected from infants and mothers, and information on periconceptional smoking history was obtained from maternal interviews, as part of the National Birth Defects Prevention Study. We analyzed five polymorphisms in three genes that code for enzymes involved in metabolism of some cigarette smoke constituents (CYP1A1, CYP1A2, and NAT2). Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) independently for maternal smoking and maternal and infant gene variants, and to assess joint associations of maternal smoking and maternal or infant gene variants with gastroschisis. In analyses adjusted for maternal age at delivery and stratified by maternal race-ethnicity, we identified three suggestive associations among 30 potential associations with sufficient numbers to calculate ORs: CYP1A1*2A for non-Hispanic white mothers who smoked periconceptionally (aOR = 0.38, 95% CI 0.15-0.98), and NAT2*6 for Hispanic non-smoking mothers (aOR = 2.17, 95% CI 1.12-4.19) and their infants (aOR = 2.11, 95% CI 1.00-4.48). This analysis does not support the occurrence of effect modification between periconceptional maternal smoking and most of the xenobiotic metabolizing enzyme gene variants assessed.

Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study.

BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). CONCLUSION: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

Cueing and gait improvement among people with Parkinson's disease: a meta-analysis.

OBJECTIVE: To compare the relative efficacy of visual versus auditory cueing on gait among individuals with Parkinson's disease (PD). DATA SOURCES: A systematic search was completed up to September 2011, using the following databases: EMBASE, Scopus, Medline, CINAHL, and PubMed. STUDY SELECTION: Four authors searched the databases using the following terms: Parkinson's disease (including abbreviations), gait, cadence, step, pace, cueing, cues, and prompt. All studies that evaluated the effect of cueing on gait in PD were selected by consensus of 2 pairs of authors who reviewed the titles and abstracts. Each pair of authors then applied the inclusion and exclusion criteria to each study, and 25 articles were chosen. Inclusion criteria were cueing studies that reported pre- and postoutcome measures of gait parameters. Exclusion criteria were lack of data and studies that evaluated gait aids. DATA EXTRACTION: Gait measures of cadence, stride length, and velocity, before and after cueing, were collected from each study. If data were represented in graphs, a pair of authors extracted the data points individually, then compared and averaged values. DATA SYNTHESIS: The data were synthesized using a meta-analysis based on cue type. Auditory cueing demonstrated significant improvement of cadence (Hedge g=.556; 95% confidence interval [CI], .291-.893), stride length (Hedge g=.497; 95% CI, .289-.696), and velocity (Hedge g=.544; 95% CI, .294-.795). In contrast, visual cueing significantly improved stride length only (Hedge g=.554; 95% CI, .072-1.036). CONCLUSIONS: The findings suggest that auditory cueing is more effective for treating gait disorders in PD. Further research is needed to determine the optimum auditory cueing strategy for gait improvements.