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.

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.

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.

Multicenter Test of an Emergency Department Trigger Tool for Detecting Adverse Events.

OBJECTIVES: Traditional approaches to safety and quality screening in the emergency department (ED) are porous and low yield for identifying adverse events (AEs). A better approach may be in the use of trigger tool methodology. We recently developed a novel ED trigger tool using a multidisciplinary, multicenter approach. We conducted a multicenter test of this tool and assess its performance. METHODS: In design and participants, we studied the ED trigger tool for a 13-month period at four EDs. All patients 18 years and older with Emergency Severity Index acuity levels of 1 to 3 seen by a provider were eligible. Reviewers completed standardized training modules. Each site reviewed 50 randomly selected visits per month. A first-level reviewer screened for presence of predefined triggers (findings that increase the probability of an AE). If no trigger is present, the review is deemed complete. When present, a trigger prompts an in-depth review for an AE. Any event identified is assigned a level of harm using the Medication Event Reporting and Prevention (MERP) Index, ranging from a near miss (A) to patient death (I). Events are noted as present on arrival or in the ED, an act of commission or omission, and are assigned one of four event categories. A second-level physician performs a confirmatory review of all AEs and independently reviews 10% of cases to estimate the false-negative rate. All AEs or potential AEs were reviewed in monthly group calls for consensus on findings. The primary outcome is the proportion of visits in which an AE is identified, overall and by site. Secondary outcomes include categories of events, distribution of harm ratings, and association of AEs with sociodemographic and clinical factors and triggers. We present sociodemographic data and details about AEs and results of logistic regression for associations of AEs with of triggers, sociodemographics, and clinical variables. RESULTS: We captured 2594 visits that are representative, within site, of their patient population. Overall, the sample is 64% white, 54% female, and with a mean age of 51. Variability is observed between sites for age, race, and insurance, but not sex. A total of 240 events were identified in 228 visits (8.8%) of which 53.3% were present on arrival, 19.7% were acts of omission, and 44.6% were medication-related, with some variability across sites. A MERP F score (contributing to need for admission, higher level of care, or prolonged hospitalization) was the most common severity level (35.4% of events). Overall, 185 (77.1%) of 240 events involved patient harm (MERP level ≥ E), affecting 175 visits (6.7%). Triggers were present in 951 visits (36.6%). Presence of any trigger was strongly associated with an AE (adjusted odds ratio = 4.6, 95% confidence interval = 3.2-6.6). Ten triggers were individually associated with AEs (adjusted odds ratio = 2.1-7.7). Variability was observed across sites in individual trigger associations, event rates, and categories, but not in severity ratings of events. The overall false-negative rate was 6.1%. CONCLUSIONS: The trigger tool approach was successful in identifying meaningful events. The ED trigger tool seems to be a promising approach for identifying all-cause harm in the ED.

The Emergency Department Trigger Tool: Validation and Testing to Optimize Yield.

OBJECTIVE: Recognized as a premier approach for adverse event (AE) detection, trigger tools have been developed for multiple clinical settings outside the emergency department (ED). We recently derived and tested an ED trigger tool (EDTT) with enhanced features for high-yield detection of harm, consisting of 30 triggers associated with AEs. In this study, we validate the EDTT in an independent sample and compare record selection approaches to optimize yield for quality improvement. METHODS: This is a retrospective observational study using data from 13 months of visits to an urban, academic ED by patients aged ≥ 18 years (92,859 records). We conducted standard two-tiered trigger tool reviews on an independent validation sample of 3,724 records with at least one of the 30 triggers found associated with AEs in our previous derivation sample (N = 1,786). We also tested three new candidate triggers and reviewed 72 records with no triggers for comparison purposes. We compare derivation and validation samples on: 1) triggers showing persistent associations with AEs, 2) AE yield (AEs detected/records reviewed), and 3) representativeness of AE types detected. We use bivariate associations of triggers with AEs as the basis for trigger selection. We then use multivariable modeling in the combined derivation and validation samples to determine AE risk scores using trigger weights. This allows us to predict occurrence of AEs and derive population prevalence estimates. Finally, we compare yield for detection of AEs under three record selection strategies (random selection, trigger counts, weighted trigger counts). RESULTS: Twenty-four of the 30 triggers were confirmed to be associated with AEs on bivariate testing. Three previously marginal triggers and two of three new candidate triggers were also found to be associated with AEs. The presence of any of these 29 triggers was associated with an AE rate of 10% in our selected sample (compared to 1.1% for none, p < 0.001). The risk of an AE increased with number of triggers. Combining data from both phases, we identified 461 AEs in 429 unique visits in 5,582 records reviewed. Our multivariable model (which emphasized parsimony) retained 12 triggers with a ROC AUC of 82% in both samples. Selecting records for review based on number of triggers improves yield to 14% for 4+ triggers (top 10% of visits) and to 28% for 8+ (top 1%). A weighted trigger count has corresponding yields of 18 and 38%. The method for selecting records for review did not appear to affect event-type representativeness, with similar distributions of event types and severities detected. CONCLUSIONS: In this single-site study of the EDTT we observed high levels of validity in trigger selection, yield, and representativeness of AEs, with yields that are superior to estimates for traditional approaches to AE detection. Record selection using weighted triggers outperforms a trigger count threshold approach and far outperforms random sampling from records with at least one trigger. The EDTT is a promising efficient and high-yield approach for detecting all-cause harm to guide quality improvement efforts in the ED.

Adverse Events Present on Arrival to the Emergency Department: The ED as a Dual Safety Net.

BACKGROUND: The emergency department (ED) is the natural venue for the provision of acute unscheduled care. However, little is known about the nature and proportion of this care that goes to addressing adverse events (AEs)-physical injury to a patient due to health care that requires some intervention-that are present on arrival (POA) to the ED. Described here are AEs that are POA, and population prevalence estimates for these events. METHODS: This retrospective observational study tested the ED Trigger Tool, using data from an urban academic medical center. Patients aged ≥18 completing an ED visit were eligible (N = 92,859). A total of 5,582 visits with triggers (findings that increase the likelihood of an AE) were reviewed using the two-tier trigger approach. AEs were categorized by severity, type, and whether they were POA. POA AEs, and sociodemographic and trigger associations with AEs are described. RESULTS: Of 1,181 AEs identified, 718 (60.8%) were POA to the ED. Patients with POA AEs were more often white (51.1% vs. 39.7%, p < 0.001) and older (median age 62 vs. 50, p < 0.001). The majority of POA AEs were medication-related and patient care-related events. In the population at this center, POA AEs account for an estimated 7.6% of ED visits (95% confidence interval = 6.9%-8.2%). CONCLUSION: In this single-center study, the majority of AEs detected using the ED Trigger Tool were POA. These findings highlight the importance of the ED as a safety net for harm occurring across the health system.

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.

Critical Review, Development, and Testing of a Taxonomy for Adverse Events and Near Misses in the Emergency Department.

OBJECTIVES: An adverse event (AE) is a physical harm experienced by a patient due to health care, requiring intervention. Describing and categorizing AEs is important for quality and safety assessment and identifying areas for improvement. Safety science suggests that improvement efforts should focus on preventing and mitigating harm rather than on error, which is commonplace but infrequently leads to AEs. Most taxonomies fail to describe harm experienced by patients (e.g., hypoxia, hemorrhage, anaphylaxis), focusing instead on errors, and use categorizations that are too broad to be useful (e.g., "communication error"). We set out to create a patient-centered, emergency department (ED)-specific framework for describing AEs and near misses to advance quality and safety in the acute care setting. METHODS: We performed a critical review of existing taxonomies of harm, evaluating their applicability to the ED. We identified and adopted a classification framework and developed a taxonomy using an iterative process categorizing approximately 600 previously identified AEs and near misses. We reviewed this taxonomy with collaborators at four medical centers, receiving feedback and providing clarification. We then disseminated a set of representative scenarios for these safety experts to categorize independently using the taxonomy. We calculated interrater reliability and performance compared to our criterion standard. RESULTS: Our search identified candidate taxonomies for detailed review. We selected the Adventist Health Systems AE taxonomy and modified this for use in the ED, adopting a framework of categories, subcategories, and up to three modifiers to further describe events. On testing, overall reviewer agreement with the criterion standard was 92% at the category level and 88% at the subcategory level. Three of the four raters concurred in 55 of 59 scenarios (93%) and all four concurred in 46 of 59 scenarios (78%). At the subcategory level, there was complete agreement in 40 of 59 (68%) scenarios and majority agreement in 55 of 59 instances (93%). Performance of individual raters ranged from very good (88%, 52/59) to near perfect (98%, 58/59) at the main category level. CONCLUSIONS: We developed a taxonomy of AEs and near misses for the ED, modified from an existing framework. Testing of the tool with minimal training yielded high performance and good inter-rater reliability. This taxonomy can be adapted and modified by EDs seeking to enhance their quality and safety reviews and characterize harm occurring in their EDs for quality improvement purposes.

Within-Family Effects of Smoking during Pregnancy on ADHD: the Importance of Phenotype.

We sought to test within- and between- family associations of smoking during pregnancy (SDP) and attention deficit-hyperactivity disorder (ADHD) symptoms using a structured interview based on the conventional Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) symptoms and the Strengths and Weaknesses of ADHD-Symptoms and Normal-Behavior (SWAN) scale, which is a population based measure that grew out of the notion that an ADHD diagnosis exists on the extreme end of a continuum of normative behaviors and includes both above- and below- average performance on attention and activity. We used a sibling-comparison approach in a sample of 173 families including siblings aged 7-16 years (52% male) drawn from the state of Missouri, USA, wherein mothers smoked during one pregnancy but not the other. There was a within-family effect of smoking during pregnancy on SWAN hyperactivity/impulsivity and SWAN total ADHD behaviors. The associations between SDP and DSM-IV-based ADHD symptom dimensions as well as SWAN inattention were explained by familial confounds. These findings suggest that SDP exerts a potentially causal effect on increased ADHD hyperactive/impulsive behaviors and that this SDP effect is best captured when hyperactivity/impulsivity is assessed more normatively across the population, rather than specifically assessing problematic behaviors via DSM symptoms. Thus, any potentially causal effect of SDP on ADHD symptom dimensions may be restricted to hyperactive/impulsive behaviors rather than inattention, and normative, non-DSM-IV based behavioral measures may provide a more sensitive test of mechanisms of SDP-ADHD symptom associations, particularly in non-clinical samples.

Inhibitory control in siblings discordant for exposure to maternal smoking during pregnancy.

Maternal smoking during pregnancy (SDP) has been linked to poorer offspring executive function across development, but SDP does not occur independent of other familial risk factors. As such, poor and inconsistent control for potential confounds, notably shared familial (i.e., genetic and environmental) confounds, preclude concluding causal effects of SDP on child outcomes. We examined the within-family association between SDP and one component of executive function, inhibitory control, in a sample of families (N = 173) specifically selected for sibling pairs discordant for exposure to SDP. Thus, the present study examines if the SDP-inhibitory control association withstands rigorous control for potential child and familial confounds. 79% of the variation in child inhibitory control was attributable to within-family differences and 21% was attributable to differences between families, indicating that the variability in inhibitory control was primarily a function of differences between siblings rather than differences across families. Further, the association between SDP and inhibitory control was fully attenuated when confounds were considered. These findings suggest that co-occurring vulnerabilities act as more salient risk factors for poorer child inhibitory control than SDP and may serve as effective targets of interventions seeking to improve children's inhibitory control in families with nicotine dependent mothers. (PsycINFO Database Record

Prenatal Exposure Effects on Early Adolescent Substance Use: Preliminary Evidence From a Genetically Informed Bayesian Approach.

OBJECTIVE: Given the controversy surrounding the question of whether there are direct or causal effects of exposure to maternal smoking during pregnancy (SDP) on offspring outcomes such as substance use during the adolescent years, we sought to test, on a preliminary basis, within- and between-family associations of SDP and initiation of substance use early in adolescence (by age 15 years) using a discordant sibling design. METHOD: We used a sibling-comparison approach in a sample of 173 families drawn from the state of Missouri, wherein mothers were discordant for smoking behaviors between two different pregnancies, to test for associations of SDP and initiation of substance use in a younger adolescent cohort. The discordant sibling comparison approach allows for disentangling familial effects from direct effects of SDP through the purposeful collection of data from siblings within the same family with differential exposure. RESULTS: There were no between- or within-family effects of SDP on initiation of any type of substance use (alcohol, marijuana, smoking, and other drug classes), suggesting that SDP does not exert a direct effect on substance use in early adolescence. CONCLUSIONS: Preliminary findings did not support an association of SDP and initiation of substance use in this younger adolescent sample. Studies such as this one can help build a body of evidence to explain whether associations of SDP and adolescent outcomes reflect a direct effect of SPD or may instead be attributable to familial confounders that are controlled in the discordant sibling design.

The variance shared across forms of childhood trauma is strongly associated with liability for psychiatric and substance use disorders.

INTRODUCTION: Forms of childhood trauma tend to co-occur and are associated with increased risk for psychiatric and substance use disorders. Commonly used binary measures of trauma exposure have substantial limitations. METHODS: We performed multigroup confirmatory factor analysis (CFA), separately by sex, using data from the Childhood Trauma (CT) Study's sample of twins and siblings (N = 2594) to derive three first-order factors (childhood physical abuse, childhood sexual abuse, and parental partner abuse) and, as hypothesized, one higher order, childhood trauma factor (CTF) representing a measure of their common variance. RESULTS: CFA produced a good-fitting model in the CT Study; we replicated the model in the Comorbidity and Trauma (CAT) Study's sample (N = 1981) of opioid-dependent cases and controls. In both samples, first-order factors are moderately correlated (indicating they measure largely unique, but related constructs) and their loadings on the CTF suggest it provides a reasonable measure of their common variance. We examined the association of CTF score with risk for psychiatric and substance use disorders in these samples and the OZ-ALC GWAS sample (N = 1538) in which CT Study factor loadings were applied. We found that CTF scores are strongly associated with liability for psychiatric and substance use disorders in all three samples; estimates of risk are extremely consistent across samples. CONCLUSIONS: The CTF is a continuous, robust measure that captures the common variance across forms of childhood trauma and provides a means to estimate shared liability while avoiding multicollinearity.

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.

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).

Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults.

OBJECTIVES: Studies have reported an association between serotonin reuptake inhibitors (SRIs) and accelerated bone loss. Genetic variation in the serotonin system might modulate bone metabolism changes during SRI treatment. In a clinical trial we examined functional genetic polymorphisms of serotonin transporter and receptors involved in bone metabolism to determine whether they predict changes in bone metabolism during SRI treatment. METHODS: In 69 adults (age ≥ 60) participating in a 12-week, open-label trial of the SRI venlafaxine for major depression, serum markers of bone formation (P1NP) and resorption (ß-CTX) were assayed before and after treatment. Participants were genotyped for putative high- versus low-expressing polymorphisms in the serotonin transporter (5HTTLPR) and 1B receptor (HTR1B) genes. RESULTS: Bone formation was significantly reduced with administration of venlafaxine in participants with the high-expressing 5HTTLPR genotype and those with the low-expressing HTR1B genotype. This primarily occurred in individuals with the combination of the high-expressing 5HTTLPR genotype and the low-expressing HTR1B genotype. CONCLUSIONS: These preliminary findings indicate that genetic variation in the serotonin receptors predicts changes in bone metabolism during SRI use. If these results are replicated and clinically confirmed, we will have identified a genetic subgroup at high risk for deleterious bone outcomes with the use of SRIs.

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.

Attention-Deficit/Hyperactivity Disorder, Autistic Traits, and Substance Use Among Missouri Adolescents.

BACKGROUND: Although existing literature demonstrates the association of attention-deficit/hyperactivity disorder (ADHD) with both substance use (SU) and autism spectrum disorder (ASD), few studies have examined rates of SU among adolescents with elevated ASD symptoms, with or without comorbid ADHD. Clinic-based studies suggest a possible protective effect of ASD against SU, but this has not been confirmed in population-based studies. OBJECTIVE: We examined alcohol, tobacco, and drug use in adolescents with either ADHD, elevated autistic traits, or both as compared with controls. METHODS: Subjects (N = 2937) who were 13 to 17 years old from a Missouri population-based large sibship sample were assessed for ADHD, autistic traits, and SU with the use of parent-report questionnaires. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD symptom criterion (Criterion A) was applied to the Strengths and Weaknesses of ADHD-symptoms and Normal-behavior (SWAN) questionnaire item responses to determine ADHD diagnosis. The presence of elevated autistic traits was defined as a raw Social Responsiveness Scale (SRS) score of 62 (95th percentile for this sample) or higher. SU was determined with the use of three items from the Child Behavior Checklist (CBCL). Statistical methods used included logistic and fractional polynomial regression. RESULTS: As compared with controls, adolescents with ADHD were at increased risk for alcohol, tobacco, and drug use whether or not they had elevated autistic traits. Adolescents with elevated autistic traits were at significantly increased risk for drug use other than alcohol and tobacco, even if they did not have ADHD. Among those with raw SRS scores in the range of about 20 (normal) to 80 (consistent with mild to moderate ASD), adolescents with ADHD had higher levels of SU than control individuals with similar levels of autistic traits. However, strong conclusions cannot be drawn regarding individuals with very low or very high SRS scores as a result of sparse data. CONCLUSIONS: This study confirms previous research showing an increased risk of SU among adolescents with ADHD. It also provides new information indicating that adolescents with high levels of autistic traits are at elevated risk for alcohol and tobacco use if they have comorbid ADHD; in addition, they may be at high risk for other drug use, even if they do not have comorbid ADHD. Therefore, it should not be assumed that adolescents with mild to moderate ASD have a low risk of SU, especially if ADHD is also present.

Exploration of ADHD Subtype Definitions and Co-Occurring Psychopathology in a Missouri Population-Based Large Sibship Sample.

BACKGROUND: There is some debate regarding the utility of Attention-Deficit/ Hyperactivity Disorder (ADHD) subtypes as currently defined. Differences in co-occurring psychopathology among subtypes would support the validity of subtype definitions. OBJECTIVE: To explore how ADHD subtype relates to co-occurring psychopathology in a large population-based sample of children and adolescents (n=5744). METHOD: Parents completed the Strengths and Weaknesses of ADHD-symptoms and Normal behavior (SWAN) questionnaire, the Child Behavior Checklist (CBCL) and the Social Responsiveness Scale (SRS). Methods including discriminant analysis, principal components analysis, and fractional polynomial regression were used to examine the relationship between ADHD diagnostic subtypes and co-occurring psychopathology. RESULTS: Children with different ADHD subtypes show differences on several CBCL subscales. A combination of CBCL subscales and SRS score had good ability to discriminate ADHD subtypes. Conversely, for the same overall number of ADHD symptoms, individuals who present with both inattentive and hyperactive/impulsive symptoms exhibit higher severity of co-occurring psychopathology on a summary measure derived from principal components analysis of the CBCL subscales and SRS. This includes some subjects who fail to meet the DSM-IV-TR ADHD symptom criterion due to having less than 6 inattentive and less than six hyperactive-impulsive symptoms, yet have ADHD symptom severity similar to those with the inattentive or hyperactive-impulsive subtype. CONCLUSIONS: Several convergent lines of analysis provide support for the continued use of ADHD subtypes (or current presentation symptom profiles), as evidenced by differences in co-existing psychopathlogy. We also found that current diagnostic criteria may fail to identify a potentially impaired group of individuals who have low-to-moderate levels of both inattention and hyperactivity/impulsivity. Under the upcoming DSM-5, it will be important for clinicians to consider the option of giving an ADHD "not elsewhere classified" diagnosis to such children.

ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure.

CONTEXT: The genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging. OBJECTIVE: To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs) with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations. DESIGN: Case-control genetic association study that included 2 control groups (lacking an established optimal control group). SETTING: Semistructured psychiatric interviews. PARTICIPANTS: A total of 1459 Australian cases ascertained from opioid replacement therapy clinics, 531 neighborhood controls ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and 1495 unrelated Australian Twin Registry controls not dependent on alcohol or illicit drugs selected from a twin and family sample. MAIN OUTCOME MEASURE: Lifetime heroin dependence. RESULTS: Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (P ≥ .01); a similar comparison with neighborhood controls revealed greater differences (P ≥ 1.8 × 10(-4)). Comparing cases (n = 1459) with the subgroup of neighborhood controls not dependent on illicit drugs (n = 340), 3 SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 (most strongly associated; odds ratio = 1.59; 95% CI, 1.32-1.92; P = 9.7 × 10(-7)), ANKK1 SNP rs4938013, and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (n = 191) and nondependent (n = 340) neighborhood controls, suggesting that liability likely extends to nonopioid illicit drug dependence. Aggregate heroin dependence risk associated with 2 SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (P = 2.7 × 10(-9) for the risk-associated linear trend). CONCLUSIONS: Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence.

Examining the association of NRXN3 SNPs with borderline personality disorder phenotypes in heroin dependent cases and socio-economically disadvantaged controls.

BACKGROUND: Borderline personality disorder (BPD) and substance use disorders frequently co-occur; their dual presence predicts poor prognosis. The genetic underpinnings of BPD have not been well-characterized and could offer insight into comorbidity. The current report focuses on the association of neurexin 3 (NRXN3) single nucleotide polymorphisms (SNPs) with BPD symptoms in heroin dependent cases and controls. METHODS: The sample of the Comorbidity and Trauma Study, a genetic association study of heroin dependence, consists of Australian heroin dependent cases ascertained from opioid replacement therapy clinics and controls ascertained in nearby economically disadvantaged neighborhoods. The assessment included a screening instrument for BPD, used previously in Australian population surveys. Genotypic and BPD phenotypic data were available for 1439 cases and 507 controls. We examined the association of 1430 candidate gene SNPs with BPD phenotypes. RESULTS: One or more NRXN3 SNPs were nominally associated with all BPD phenotypes; however, none met the conservative significance threshold we employed to correct for multiple testing. The most strongly associated SNPs included rs10144398 with identity disturbance (p=4.9×10(-5)) and rs10151731 with affective instability (p=8.8×10(-5)). The strongest association with screening positive for BPD was found for the NRXN3 SNP, rs10083466 (p=.0013). Neither the correlation of BPD phenotypes nor the linkage disequilibrium relationships of the SNPs account for the number of observed associations involving NRXN3 SNPs. CONCLUSIONS: Our findings provide intriguing preliminary evidence for the association of NRXN3 with BPD phenotypes. The strongest associations were found for traits (i.e., affective instability; identity disturbance) also observed with other disorders.