Emergency Department Adverse Events Detected Using the Emergency Department Trigger Tool.

STUDY OBJECTIVE: The Emergency Department Trigger Tool (EDTT) is a novel approach to adverse event detection in the ED. We previously described the derivation, validation, and high-level performance of this tool. Here we further detail adverse events detected to demonstrate the utility of the EDTT and how it might be used for quality improvement. METHODS: This is a secondary analysis of data from a retrospective observational study. We ran the EDTT (a computerized query for triggers) on 13 months of ED visit data, reviewing 5,582 selected records using a typical 2-tiered trigger tool approach. The adverse events detected were categorized by place of occurrence (in the ED versus present on arrival), severity, omission/commission, and type using a taxonomy with categories, subcategories, and up to 3 cross-cutting modifiers. We present adverse event data in detail, focusing in turn on each of these descriptors (severity, event types, and cross-cutting themes) and highlight opportunities identified for targeted improvement. RESULTS: We identified 458 adverse events occurring in the ED for a 13-month period, 10% of which required urgent intervention. Nearly all (90%) were acts of commission. Events resulting in harm were most often related to medications administered and patient care. Common cross-cutting event types included adverse events related to bleeding, opioids, and the use of propofol. Most adverse events (80%) led to temporary harm. CONCLUSION: The EDTT identifies a broad spectrum of adverse event types, allowing a review by severity, frequency, and type to better understand existing levels of harm in the ED and identify targets for quality improvement. A multicenter study of the EDTT is currently underway, which will contribute additional power and assess generalizability.

The impact of a perceptual learning module on novices' ability to visually estimate left ventricular ejection fraction by transesophageal echocardiography: a randomized controlled study.

PURPOSE: Echocardiography is a difficult tool to master. Competency requires the supervised interpretation of hundreds of exams. Perceptual learning modules (PLMs) are novel learning tools that aim to speed up this learning process by enabling learners to go online and interpret numerous clinical images, followed systematically by expert feedback. We developed and tested a PLM aimed at improving novices' ability to quickly visually estimate left ventricular ejection fraction (LVEF) on transesophageal echocardiography images, a critical skill in acute care. We hypothesized that using the PLM would improve the accuracy and the speed of learners' estimations. METHODS: Learners without echocardiography experience were randomly assigned to a group that used the 96-case PLM (n = 26) or a control group (n = 26) that did not. Both groups took a pre-test and an immediate post-test that measured the accuracy of their visual estimations during a first session. At six months, participants also completed a delayed post-test. RESULTS: In the immediate post-test, the PLM group showed significantly better accuracy than the control group (median absolute estimation error 6.1 vs 9.0; difference 95% CI, 1.0 to 4.6; P < 0.001). Nevertheless, at six months, estimation errors were similar in both groups (median absolute estimation error 10.0 vs 10.0; difference 95% CI, -1.3 to 2.1; P = 0.27). CONCLUSIONS: Participation in a short online PLM significantly improved novices' short-term ability to accurately estimate LVEF visually, compared with controls. The effect was not sustained at six months. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03245567); registered 7 August 2017.

RéSUMé: OBJECTIF: L'échocardiographie est un outil difficile à maîtriser. Afin d'acquérir cette compétence, l'interprétation supervisée de centaines d'examens est nécessaire. Les modules d'apprentissage perceptuel (MAP) sont des outils d'apprentissage innovants qui visent à accélérer ce processus d'apprentissage en permettant aux apprenants d'aller en ligne et d'interpréter de nombreuses images cliniques, lesquelles sont systématiquement suivies par des rétroactions d'experts. Nous avons mis au point et testé un MAP visant à améliorer la capacité des nouveaux apprenants à rapidement estimer visuellement la fraction d'éjection ventriculaire gauche (FEVG) sur des images d'échocardiographie transœsophagienne, une compétence critique dans les soins aigus. Nous avons émis l'hypothèse que l'utilisation du MAP améliorerait la précision et la rapidité des estimations des apprenants. MéTHODE: Les apprenants sans expérience de lecture d'échocardiographie ont été aléatoirement alloués à un groupe qui a utilisé le MAP de 96 cas (n = 26) ou à un groupe témoin (n = 26) qui ne l'a pas utilisé. Les deux groupes ont passé un prétest et un post-test immédiat qui ont mesuré l'exactitude de leurs estimations visuelles au cours d'une première séance. Six mois plus tard, les participants ont également passé un autre post-test retardé. RéSULTATS: Dans le post-test immédiat, le groupe MAP a démontré une précision significativement meilleure que le groupe témoin (erreur d'estimation absolue médiane, 6,1 vs 9,0; différence de l'IC 95 %, 1,0 à 4,6; P < 0,001). Néanmoins, à six mois, les erreurs d'estimation étaient similaires dans les deux groupes (erreur d'estimation absolue médiane, 10,0 vs 10,0; différence de l'IC 95 %, -1,3 à 2,1; P = 0,27). CONCLUSION: La participation à un bref MAP en ligne a considérablement amélioré la capacité à court terme des nouveaux apprenants à estimer visuellement et avec précision la FEVG, par rapport à un groupe témoin. L'effet n'était pas maintenu à six mois. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT03245567); enregistrée le 7 août 2017.

The Emergency Department Trigger Tool: A Novel Approach to Screening for Quality and Safety Events.

STUDY OBJECTIVE: Trigger tools improve surveillance for harm by focusing reviews on records with "triggers" whose presence increases the likelihood of an adverse event. We refine and automate a previously developed emergency department (ED) trigger tool and present record selection strategies to further optimize yield. METHODS: We specified 97 triggers for extraction from our electronic medical record, identifying 76,894 ED visits with greater than or equal to 1 trigger. We reviewed 1,726 records with greater than or equal to 1 trigger, following a standard trigger tool review process. We validated query performance against manual review and evaluated individual triggers, retaining only those associated with adverse events in the ED. We explored 2 approaches to enhance record selection: on number of triggers present and using trigger weights derived with least absolute shrinkage and selection operator logistic regression. RESULTS: The automated query performed well compared with manual review (sensitivity >70% for 80 triggers; specificity >92% for all). Review yielded 374 adverse events (21.6 adverse events per 100 records). Thirty triggers were associated with risk of harm in the ED. An estimated 10.3% of records with greater than 1 of these triggers would include an adverse event in the ED. Selecting only records with greater than or equal to 4 or greater than or equal to 9 triggers improves yield to 17% and 34.8%, respectively, whereas use of least absolute shrinkage and selection operator trigger weighting enhances the yield to as high as 52%. CONCLUSION: The ED trigger tool is a promising approach to improve yield, scope, and efficiency of review for all-cause harm in emergency medicine. Beginning with a broad set of candidate triggers, we validated a computerized query that eliminates the need for manual screening for triggers and identified a refined set of triggers associated with adverse events in the ED. Review efficiency can be further enhanced with enhanced record selection.

Disruptive Behavior in Siblings Discordant for Exposure to Maternal Smoking During Pregnancy: A Multi-rater Approach.

INTRODUCTION: Maternal smoking during pregnancy (SDP) is associated with disruptive behavior. However, there is debate whether the SDP-disruptive behavior association is a potentially causal pathway or rather a spurious effect confounded by shared genetic and environmental factors. AIMS AND METHODS: The Missouri Mothers and Their Children Study is a sibling comparison study that includes families (n = 173) selected for sibling pairs (aged 7-16 years) discordant for SDP. Critically, the sibling comparison design is used to disentangle the effects of SDP from familial confounds on disruptive behavior. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount of SDP). Multiple informants (parents and teachers) reported on disruptive behavior (i.e., DSM-IV semi-structured interview, the Child Behavior Checklist, and Teacher Report Form). RESULTS: The variability in disruptive behavior was primarily a function of within-family differences (66%-100%). Consistent with prior genetically informed approaches, the SDP-disruptive behavior association was primarily explained by familial confounds (genetic and environmental). However, when using a multi-rater approach (parents and teachers), results suggest a potentially causal effect of SDP on disruptive behavior (b = 0.09, SE = 0.04, p = 0.03). The potentially causal effect of SDP remained significant in sensitivity analyses. DISCUSSION: These findings suggest that familial confounding likely plays a complex role in the SDP-disruptive behavior association when examining both parent and teacher reports of behavior. Importantly, the current study highlights the importance of multiple raters, reflecting a more comprehensive measure of complex behaviors (e.g., disruptive behavior) to examine the teratogenic effects of SDP. IMPLICATIONS: Our study provides additional evidence that controlling for genetic and family factors is essential when examining the effect of SDP on later behavioral problems, as it explains a portion of the association between SDP and later behavioral problems. However, we found a significant association between SDP and disruptive behavior when using a multi-rater approach that capitalizes on both parent and teacher report, suggesting that parent and teacher ratings capture a unique perspective that is important to consider when examining SDP-behavior associations.

Walking, Gross Motor Development, and Brain Functional Connectivity in Infants and Toddlers.

Infant gross motor development is vital to adaptive function and predictive of both cognitive outcomes and neurodevelopmental disorders. However, little is known about neural systems underlying the emergence of walking and general gross motor abilities. Using resting state fcMRI, we identified functional brain networks associated with walking and gross motor scores in a mixed cross-sectional and longitudinal cohort of infants at high and low risk for autism spectrum disorder, who represent a dimensionally distributed range of motor function. At age 12 months, functional connectivity of motor and default mode networks was correlated with walking, whereas dorsal attention and posterior cingulo-opercular networks were implicated at age 24 months. Analyses of general gross motor function also revealed involvement of motor and default mode networks at 12 and 24 months, with dorsal attention, cingulo-opercular, frontoparietal, and subcortical networks additionally implicated at 24 months. These findings suggest that changes in network-level brain-behavior relationships underlie the emergence and consolidation of walking and gross motor abilities in the toddler period. This initial description of network substrates of early gross motor development may inform hypotheses regarding neural systems contributing to typical and atypical motor outcomes, as well as neurodevelopmental disorders associated with motor dysfunction.

Autism-Related Variation in Reciprocal Social Behavior: A Longitudinal Study.

Deficits in reciprocal social behavior are a characterizing feature of autism spectrum disorder (ASD). Autism-related variation in reciprocal social behavior (AVR) in the general population is continuously distributed and highly heritable-a function of additive genetic influences that overlap substantially with those which engender clinical autistic syndromes. This is the first long-term prospective study of the stability of AVR from childhood through early adulthood, conducted via serial ratings using the Social Responsiveness Scale, in a cohort-sequential study involving children with ASD, other psychiatric conditions, and their siblings (N = 602, ages = 2.5-29). AVR exhibits marked stability throughout childhood in individuals with and without ASD.

Joint Attention and Brain Functional Connectivity in Infants and Toddlers.

Initiating joint attention (IJA), the behavioral instigation of coordinated focus of 2 people on an object, emerges over the first 2 years of life and supports social-communicative functioning related to the healthy development of aspects of language, empathy, and theory of mind. Deficits in IJA provide strong early indicators for autism spectrum disorder, and therapies targeting joint attention have shown tremendous promise. However, the brain systems underlying IJA in early childhood are poorly understood, due in part to significant methodological challenges in imaging localized brain function that supports social behaviors during the first 2 years of life. Herein, we show that the functional organization of the brain is intimately related to the emergence of IJA using functional connectivity magnetic resonance imaging and dimensional behavioral assessments in a large semilongitudinal cohort of infants and toddlers. In particular, though functional connections spanning the brain are involved in IJA, the strongest brain-behavior associations cluster within connections between a small subset of functional brain networks; namely between the visual network and dorsal attention network and between the visual network and posterior cingulate aspects of the default mode network. These observations mark the earliest known description of how functional brain systems underlie a burgeoning fundamental social behavior, may help improve the design of targeted therapies for neurodevelopmental disorders, and, more generally, elucidate physiological mechanisms essential to healthy social behavior development.

Anticoagulation Obtained below the Arterial Clamp Using a Single Fixed Bolus of Heparin in Vascular Surgery: A Pilot Study.

BACKGROUND: No clear recommendations exist regarding the optimal dosing of unfractionated heparin (UFH) during vascular surgery. Moreover, little is known about the effect of the UFH bolus downstream of the arterial clamp, where stasis and inflammation can possibly alter the anticoagulation obtained. METHODS: The aim of our prospective observational study was to assess anticoagulation below the arterial clamp and its clinical impact on the quality of revascularization. Thirty-six patients American Society of Anaesthesiologists physical status (ASA) grade I-III undergoing open revascularization surgeries were included. A baseline activated coagulation time (ACT) was obtained. Thirty minutes after a single bolus of 5,000 units of UFH, we measured an upstream ACT via a radial arterial catheter and an ACT below the arterial clamp via surgeon sampling. The quality of revascularization was assessed with preoperative and postoperative ankle-brachial and toe-brachial indexes (TBIs). RESULTS: The upstream postheparin ACT was significantly higher than the downstream postheparin ACT, with a mean difference of 24.3 sec (P < 0.0001). In 7 patients, the downstream ACT was lower than the baseline ACT. The upstream and downstream heparin concentrations were similar. There was no relationship between the downstream ACT and either ankle-brachial index improvement (28 patients, P = 0.51) or TBI improvement (27 patients, P = 0.21). CONCLUSIONS: Our study demonstrates a significant difference between the ACT above and below the arterial clamp without any clinical impact of this possibly insufficient anticoagulation. Further investigations are warranted to determine the optimal dose of UFH in vascular surgery. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02477072.

Smoking during pregnancy and ADHD risk: A genetically informed, multiple-rater approach.

Maternal smoking during pregnancy (SDP) is a significant public health concern with adverse consequences to the health and well-being of the developing child, including behavioral outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD). There is substantial interest in understanding the nature of this reported association, particularly in light of more recent genetically informed studies that suggest that the SDP-ADHD link is less clear than once thought. In a sample of families (N = 173) specifically selected for sibling pairs discordant for prenatal smoking exposure, we use a sibling-comparison approach that controls for shared genetic and familial influences to assess the effects of SDP on ADHD symptom dimensions. ADHD was measured by both parent and teacher report on the Conners report forms and the Child Behavior Checklist/Teacher Report Form (CBCL/TRF). Results for the CBCL/TRF Total ADHD score are consistent with prior genetically informed approaches and suggest that previously reported associations between SDP and ADHD are largely due to familial confounding rather than causal teratogenic effects. However, results from the Conners parent report suggest a potentially causal effect of SDP on hyperactive/impulsive and, to a lesser extent, total ADHD symptoms; SDP results in increased parent-reported hyperactive/impulsive and total ADHD symptoms even after accounting for genetic and familial confounding factors. This suggests that the Conners assessment (parent-report) may provide a sensitive measure for use in studies examining child specific SDP effects on continuous and dimensional aspects of ADHD. © 2016 Wiley Periodicals, Inc.

Unopposed cathepsin G, neutrophil elastase, and proteinase 3 cause severe lung damage and emphysema.

Cigarette smoking is a major factor for the development of pulmonary emphysema because it induces abnormal inflammation and a protease-rich local milieu that causes connective tissue breakdown of the lungs. As a result of its capacity to degrade lung tissue and the high risk of patients lacking α1-antitrypsin to develop emphysema, much interest has focused on neutrophil elastase (NE). Two similar neutrophil serine proteases (NSPs), cathepsin G and proteinase 3, coexist with NE in humans and mice, but their potential tissue-destructive role(s) remains unclear. Using a gene-targeting approach, we observed that in contrast to their wild-type littermates, mice deficient in all three NSPs were substantially protected against lung tissue destruction after long-term exposure to cigarette smoke. In exploring the underlying basis for disrupted wild-type lung air spaces, we found that active NSPs collectively caused more severe lung damage than did NE alone. Furthermore, NSP activities unleashed increased activity of the tissue-destructive proteases macrophage elastase (matrix metalloproteinase-12) and gelatinase B (matrix metalloproteinase-9). These in vivo data provide, for the first time, compelling evidence of the collateral involvement of cathepsin G, NE, and proteinase 3 in cigarette smoke-induced tissue damage and emphysema. They also reveal a complex positive feed-forward loop whereby these NSPs induce the destructive potential of other proteases, thereby generating a chronic and pathogenic protease-rich milieu.

I-gel Versus LMA-Fastrach Supraglottic Airway for Flexible Bronchoscope-Guided Tracheal Intubation Using a Parker (GlideRite) Endotracheal Tube: A Randomized Controlled Trial.

BACKGROUND: The I-gel (IG) supraglottic airway device is a reliable way to establish an airway. Its large ventilation lumen allows for easy passage of an endotracheal tube. With the use of a flexible bronchoscope, the IG offers a good visualization of the laryngeal inlet. This prospective randomized study aims to compare the success rate of flexible bronchoscope-guided tracheal intubation using either the IG or the LMA-Fastrach (FT) laryngeal masks. METHODS: One hundred twenty patients requiring general anesthesia were randomized to 1 of the 2 study groups: IG or FT. After anesthesia induction, the assigned laryngeal mask was inserted to obtain adequate ventilation. We then proceeded to a flexible bronchoscope-guided intubation through the supraglottic device. Tracheal intubation and laryngeal mask insertion success rates were noted, as well as the time required for these manipulations. The view of the laryngeal inlet was graded for each intubation attempt. RESULTS: Sixty patients were assigned to each study group. The intubation success rates were similar between the IG and the FT groups (100 % vs 95.0 % at first attempt; P = 0.12). The times required for tracheal intubation were significantly lower in the IG group (30 ± 11 seconds vs 50 ± 21 seconds; P < 0.0001). Glottic visualization was better in the IG group, with a significantly higher percentage of grade 1 visualization (63.3% vs 3.3%; P < 0.0001) and a lower percentage of grade 3 visualization (1.7% vs 60.0%; P < 0.0001), than that in the FT group. CONCLUSIONS: The use of the IG supraglottic airway device as a conduit for flexible bronchoscope-guided tracheal intubation results in a success rate equivalent to the use of the LMA-FT. However, the IG allows for shorter intubation times and a better visualization of the glottic opening compared with the LMA-FT.

Missouri Mothers and Their Children: A Family Study of the Effects of Genetics and the Prenatal Environment.

The Missouri Mothers and Their Children Study (MO-MATCH) was specifically designed to critically investigate prenatal environmental influences on child attention problems and associated learning and cognitive deficits. The project began as a pilot study in 2004 and was formally launched in 2008. Participants in the study were initially identified via the Department of Vital Statistics birth record (BR) database. Interview and lab-based data were obtained from: (1) mothers of Missouri-born children (born 1998-2005), who smoked during one pregnancy but not during another pregnancy; (2) biological fathers when available; and (3) the children (i.e., full sibling pairs discordant for exposure to maternal smoking during pregnancy (SDP). This within-mother, between-pregnancy contrast provides the best possible methodological control for many stable maternal and familial confounding factors (e.g., heritable and socio-demographic characteristics of the mother that predict increased probability of SDP). It also controls for differences between mothers who do and do not smoke during pregnancy, and their partners, that might otherwise artifactually create, or alternatively mask, associations between SDP and child outcomes. Such a design will therefore provide opportunities to determine less biased effect sizes while also allowing us to investigate (on a preliminary basis) the possible contribution of paternal or other second-hand smoke exposure during the pre, peri, and postnatal periods to offspring outcome. This protocol has developed a cohort that can be followed longitudinally through periods typically associated with increased externalizing symptoms and substance used initiation.

PTSD risk associated with a functional DRD2 polymorphism in heroin-dependent cases and controls is limited to amphetamine-dependent individuals.

Posttraumatic stress disorder (PTSD), a pathologic response to severe stress, is a common co-morbid disorder in substance-dependent individuals. Evidence from twin studies suggests that PTSD is moderately heritable. Genetic association studies to date have reported a limited number of replicated findings. We conducted a candidate gene association study in trauma-exposed individuals within the Comorbidity and Trauma Study's sample (1343 heroin-dependent cases and 406 controls from economically disadvantaged neighborhoods). After data cleaning, the 1430 single nucleotide polymorphisms (SNPs) retained for analyses provided coverage of 72 candidate genes and included additional SNPs for which association was previously reported as well as 30 ancestry-informative markers. We found a functional DRD2 promoter polymorphism (rs12364283) to be most highly associated with PTSD liability [odds ratio (OR) 1.65 (1.27-2.15); P = 1.58 × 10(-4) ]; however, this association was not significant, with a stringent Bonferroni correction for multiple comparisons. The top hits include SNPs from other dopaminergic system genes: DRD2 DRD3, TH and DBH. Additional analyses revealed that the association involving rs12364283 is largely limited to amphetamine-dependent individuals. Substantial risk is observed in amphetamine-dependent individuals, with at least one copy of this SNP [OR 2.86 (1.92-4.27); P = 2.6 × 10(-7) ]. Further analyses do not support extensive mediation of PTSD risk via self-reported impulsivity (BIS total score). These findings suggest roles for impairment in inhibitory control in the pathophysiology of PTSD and raise questions about stimulant use in certain populations (e.g. those in combat).

Association of OPRD1 polymorphisms with heroin dependence in a large case-control series.

Genes encoding the opioid receptors (OPRM1, OPRD1 and OPRK1) are obvious candidates for involvement in risk for heroin dependence. Prior association studies commonly had samples of modest size, included limited single nucleotide polymorphism (SNP) coverage of these genes and yielded inconsistent results. Participants for the current investigation included 1459 heroin-dependent cases ascertained from maintenance clinics in New South Wales, Australia, 1495 unrelated individuals selected from an Australian sample of twins and siblings as not meeting DSM-IV criteria for lifetime alcohol or illicit drug dependence (non-dependent controls) and 531 controls ascertained from economically disadvantaged neighborhoods in proximity to the maintenance clinics. A total of 136 OPRM1, OPRD1 and OPRK1 SNPs were genotyped in this sample. After controlling for admixture with principal components analysis, our comparison of cases to non-dependent controls found four OPRD1 SNPs in fairly high linkage disequilibrium for which adjusted P values remained significant (e.g. rs2236857; OR 1.25; P=2.95×10(-4) ) replicating a previously reported association. A post hoc analysis revealed that the two SNP (rs2236857 and rs581111) GA haplotype in OPRD1 is associated with greater risk (OR 1.68; P=1.41×10(-5) ). No OPRM1 or OPRK1 SNPs reached more than nominal significance. Comparisons of cases to neighborhood controls reached only nominal significance. Our results replicate a prior report providing strong evidence implicating OPRD1 SNPs and, in particular, the two SNP (rs2236857 and rs581111) GA haplotype in liability for heroin dependence. Support was not found for similar association involving either OPRM1 or OPRK1 SNPs.

The emergency department trigger tool: Multicenter trigger query validation.

OBJECTIVES: We previously described derivation and validation of the emergency department trigger tool (EDTT) for adverse event (AE) detection. As the first step in our multicenter study of the tool, we validated our computerized screen for triggers against manual review, establishing our use of this automated process for selecting records to review for AEs. METHODS: This is a retrospective observational study of visits to three urban, academic EDs over 18 months by patients ≥ 18 years old. We reviewed 912 records: 852 with at least one of 34 triggers found by the query and 60 records with none. Two first-level reviewers per site each manually screened for triggers. After completion, computerized query results were revealed, and reviewers could revise their findings. Second-level reviewers arbitrated discrepancies. We compare automated versus manual screening by positive and negative predictive values (PPVs, NPVs), present population trigger frequencies, proportions of records triggered, and how often manual ratings were changed to conform with the query. RESULTS: Trigger frequencies ranged from common (>25%) to rare (1/1000) were comparable at U.S. sites and slightly lower at the Canadian site. Proportions of triggered records ranged from 31% to 49.4%. Overall query PPV was 95.4%; NPV was 99.2%. PPVs for individual trigger queries exceeded 90% for 28-31 triggers/site and NPVs were >90% for all but three triggers at one site. Inter-rater reliability was excellent, with disagreement on manual screening results less than 5% of the time. Overall, reviewers amended their findings 1.5% of the time when discordant with query findings, more often when the query was positive than when negative (47% vs. 23%). CONCLUSIONS: The EDTT trigger query performed very well compared to manual review. With some expected variability, trigger frequencies were similar across sites and proportions of triggered records ranged 31%-49%. This demonstrates the feasibility and generalizability of implementing the EDTT query, providing a solid foundation for testing the triggers' utility in detecting AEs.

On genome-wide association studies for family-based designs: an integrative analysis approach combining ascertained family samples with unselected controls.

Large numbers of control individuals with genome-wide genotype data are now available through various databases. These controls are regularly used in case-control genome-wide association studies (GWAS) to increase the statistical power. Controls are often "unselected" for the disease of interest and are not matched to cases in terms of confounding factors, making the studies more vulnerable to confounding as a result of population stratification. In this communication, we demonstrate that family-based designs can integrate unselected controls from other studies into the analysis without compromising the robustness of family-based designs against genetic confounding. The result is a hybrid case-control family-based analysis that achieves higher power levels than population-based studies with the same number of cases and controls. This strategy is widely applicable and works ideally for all situations in which both family and case-control data are available. The approach consists of three steps. First, we perform a standard family-based association test that does not utilize the between-family component. Second, we use the between-family information in conjunction with the genotypes from unselected controls in a Cochran-Armitage trend test. The p values from this step are then calculated by rank ordering the individual Cochran-Armitage trend test statistics for the genotype markers. Third, we generate a combined p value with the association p values from the first two steps. Simulation studies are used to assess the achievable power levels of this method compared to standard analysis approaches. We illustrate the approach by an application to a GWAS of attention deficit hyperactivity disorder parent-offspring trios and publicly available controls.

Near-Miss Events Detected Using the Emergency Department Trigger Tool.

OBJECTIVES: Near misses include conditions with potential for harm, intercepted medical errors, and events requiring monitoring or intervention to prevent harm. Little is reported on near misses or their importance for quality and safety in the emergency department (ED). METHODS: This is a secondary evaluation of data from a retrospective study of the ED Trigger Tool (EDTT) at an urban, academic ED (data from October 1, 2014, to October 31, 2015; 92,859 eligible visits). All patients 18 years and older completing a visit were eligible. We ran the EDTT, a computerized query for triggers on 13 months of ED visit data, reviewing 5582 selected records using a 2-tiered approach. Events were categorized by occurrence (ED vs present on arrival [POA]), severity, omission/commission, and type, using a taxonomy with categories, subcategories, and cross-cutting modifiers. RESULTS: We identified 1458 ED near misses in 1269 of 5582 records (22.7%) and 80 near misses that were POA. Patient care events represented most ED near misses, including delays in diagnosis, treatment, and failure to monitor, primarily driven by ED boarding and crowding. Medication events were second most common (17%), including 80 medication administration errors. Of 80 POA events, 42% were related to overanticoagulation. We estimate that 19.3% of all ED visits include a near miss. CONCLUSIONS: Near-miss events are relatively common (22.7% of our sample, 19.3% in the population) and are associated with an increased risk for an adverse event. Most events were patient care related (77%) involving delays due to crowding and ED boarding followed by medication administration errors. The EDTT is a high-yield approach for detecting important near misses and latent system deficiencies that impact patient safety.

A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

Infant Visual Brain Development and Inherited Genetic Liability in Autism.

OBJECTIVE: Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings. METHODS: In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months. RESULTS: Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy. CONCLUSIONS: The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.