Bringing a developmental perspective to anxiety genetics.

Despite substantial recent advancements in psychiatric genetic research, progress in identifying the genetic basis of anxiety disorders has been limited. We review the candidate gene and genome-wide literatures in anxiety, which have made limited progress to date. We discuss several reasons for this hindered progress, including small samples sizes, heterogeneity, complicated comorbidity profiles, and blurred lines between normative and pathological anxiety. To address many of these challenges, we suggest a developmental, multivariate framework that can inform and enhance anxiety phenotypes for genetic research. We review the psychiatric and genetic epidemiological evidence that supports such a framework, including the early onset and chronic course of anxiety disorders, shared genetic risk factors among disorders both within and across time, and developmentally dynamic genetic influences. We propose three strategies for developmentally sensitive phenotyping: examination of early temperamental risk factors, use of latent factors to model underlying anxiety liability, and use of developmental trajectories as phenotypes. Expanding the range of phenotypic approaches will be important for advancing studies of the genetic architecture of anxiety disorders.

Applying VitalTalkTM Techniques to Best Case/Worst Case Training to Increase Scalability and Improve Surgeon Confidence in Shared Decision-making.

OBJECTIVE: Best Case/Worst Case (BC/WC) is a communication tool designed to promote shared decision-making for high-risk procedures near the end of life. This study aimed to increase scalability of a BC/WC training program and measure its impact on surgeon confidence in and perceived importance of the methodology. DESIGN: A prospective cohort pre-post study; December 2018 to January 2019. SETTING: Multi-center tertiary care teaching hospital. PARTICIPANTS: Forty-eight resident surgeons from general surgery and otolaryngology. RESULTS: Learners were 24 to 37 years old with 52% in post graduate year 1 to 2. Although learners encountered high-stakes communication (HSC) frequently (3.6 [0.7] on 5-point Likert scale), most reported no HSC training in medical school (74.5%) or residency (87.5%). BC/WC training was accomplished with an instructor to learner ratio of 1-to-5.3. After training, learner confidence improved on all measured communication skills on a 5-point scale (e.g., exploring patient's values increased from 3.6 [0.8] to 4.1 [0.6], p = <0.0001); average within-person improvement was 0.72 (0.6) points across all skills. Perceived importance improved across all skills (e.g., basing a recommendation on patient's values increased from 4.4 [0.8] to 4.8 [0.5], p = 0.0009); average within-person improvement was 0.46 (0.5) points across all skills. Learners reported this training would likely help them in future interactions (4.4 [0.73] on 5-point scale) and 95.2% recommended it be offered to resident physicians in other residency programs and to attending surgeons. CONCLUSIONS: Formal training in BC/WC increases learners' perception of both the importance of HSC skills and their confidence in exercising those skills in clinical practice. VitalTalkTM methodology permitted scaling training to 5.3 learners per instructor and was highly recommended for other surgeons. Ongoing training, such as this, may support more patient-centered decision-making and care.

Attention Bias to Emotional Faces Varies by IQ and Anxiety in Williams Syndrome.

Individuals with Williams syndrome (WS) often experience significant anxiety. A promising approach to anxiety intervention has emerged from cognitive studies of attention bias to threat. To investigate the utility of this intervention in WS, this study examined attention bias to happy and angry faces in individuals with WS (N = 46). Results showed a significant difference in attention bias patterns as a function of IQ and anxiety. Individuals with higher IQ or higher anxiety showed a significant bias toward angry, but not happy faces, whereas individuals with lower IQ or lower anxiety showed the opposite pattern. These results suggest that attention bias interventions to modify a threat bias may be most effectively targeted to anxious individuals with WS with relatively high IQ.

Validation of electronic health record phenotyping of bipolar disorder cases and controls.

OBJECTIVE: The study was designed to validate use of electronic health records (EHRs) for diagnosing bipolar disorder and classifying control subjects. METHOD: EHR data were obtained from a health care system of more than 4.6 million patients spanning more than 20 years. Experienced clinicians reviewed charts to identify text features and coded data consistent or inconsistent with a diagnosis of bipolar disorder. Natural language processing was used to train a diagnostic algorithm with 95% specificity for classifying bipolar disorder. Filtered coded data were used to derive three additional classification rules for case subjects and one for control subjects. The positive predictive value (PPV) of EHR-based bipolar disorder and subphenotype diagnoses was calculated against diagnoses from direct semistructured interviews of 190 patients by trained clinicians blind to EHR diagnosis. RESULTS: The PPV of bipolar disorder defined by natural language processing was 0.85. Coded classification based on strict filtering achieved a value of 0.79, but classifications based on less stringent criteria performed less well. No EHR-classified control subject received a diagnosis of bipolar disorder on the basis of direct interview (PPV=1.0). For most subphenotypes, values exceeded 0.80. The EHR-based classifications were used to accrue 4,500 bipolar disorder cases and 5,000 controls for genetic analyses. CONCLUSIONS: Semiautomated mining of EHRs can be used to ascertain bipolar disorder patients and control subjects with high specificity and predictive value compared with diagnostic interviews. EHRs provide a powerful resource for high-throughput phenotyping for genetic and clinical research.

The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function.

BACKGROUND: Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function. METHODS: We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in healthy individuals. RESULTS: Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .046). The association appeared to be stronger when early-onset (age ≤ 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p = .0048). CONCLUSIONS: Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.