Novel integrative genomic tool for interrogating lithium response in bipolar disorder

We developed a novel integrative genomic tool called GRANITE (Genetic Regulatory Analysis of Networks Investigational Tool Environment) that can effectively analyze large complex data sets to generate interactive networks. GRANITE is an open-source tool and invaluable resource for a variety of genomic fields. Although our analysis is confined to static expression data, GRANITE has the capability of evaluating time-course data and generating interactive networks that may shed light on acute versus chronic treatment, as well as evaluating dose response and providing insight into mechanisms that underlie therapeutic versus sub-therapeutic doses or toxic doses. As a proof-of-concept study, we investigated lithium (Li) response in bipolar disorder (BD). BD is a severe mood disorder marked by cycles of mania and depression. Li is one of the most commonly prescribed and decidedly effective treatments for many patients (responders), although its mode of action is not yet fully understood, nor is it effective in every patient (non-responders). In an in vitro study, we compared vehicle versus chronic Li treatment in patient-derived lymphoblastoid cells (LCLs) (derived from either responders or non-responders) using both microRNA (miRNA) and messenger RNA gene expression profiling. We present both Li responder and non-responder network visualizations created by our GRANITE analysis in BD. We identified by network visualization that the Let-7 family is consistently downregulated by Li in both groups where this miRNA family has been implicated in neurodegeneration, cell survival and synaptic development. We discuss the potential of this analysis for investigating treatment response and even providing clinicians with a tool for predicting treatment response in their patients, as well as for providing the industry with a tool for identifying network nodes as targets for novel drug discovery.     

RESILIENCE AND RECOVERY IN AMERICAN SĀMOA: A CASE STUDY OF THE 2009 SOUTH PACIFIC TSUNAMI

Case study methodology was used to explore the culturally situated response and recovery efforts following a tsunami in American Sāmoa. Data indicated that cultural mechanisms were effective in meeting physical needs but insufficient to manage the emotional trauma caused by such a large‐scale event. Samoan cultural norms strongly discourage uncontrolled emotional expression outside of ritualized grieving events. Disruptions in social networks and activities, combined with a lack of available emotional support, resulted in significant psychological distress for many survivors. Sixteen months after the tsunami residents continued to exhibit numerous symptoms of posttraumatic stress. In response to this need for emotional support, some groups within American Sāmoa are setting an example of how their culture can adapt by forging new, culturally grounded methods for addressing emotional needs that arose in the wake of the tsunami. Findings are analyzed through the lens of the social support deterioration deterrence model and activity settings theory.     

Validation of a Weight History Questionnaire to Identify Adolescent Obesity

Background

Past body weight may be a more informative factor than current weight for risk of chronic disease development. Often, investigators must rely on subject recall to gauge past body weights. The Cincinnati Weight History Questionnaire (CWHQ) was developed to aid in the retrospective identification of adults who were obese during adolescence.

Methods

To assess validity, the CWHQ was administered to a subset of National Heart, Lung, and Blood Growth and Health Study (NGHS) participants, a group of young adult females for whom historical measured anthropometrics were available. One hundred ninety-eight NGHS participants were contacted, of whom 191 (97 %) responded (age 26–29). Participants were asked to recall height and weight from ages 13 and 18, which were compared to previously measured values. Multiple indices of validity (Bland–Altman plots, sensitivity, and specificity) were calculated.

Results

The CWHQ was moderately sensitive (range, 19–66 %), but highly specific (range, 89–100 %). Recalled height and weight values used to determine body mass index (BMI) underestimated BMI based on recorded height and weight at ages 13 and 18. Differences in calculated BMI based on recalled and measured height and weight were found to increase with BMI calculated using measured values.

Conclusions

The CWHQ proved to be a moderately sensitive, but highly specific instrument for detecting adolescent obesity in a cohort of young adult females. Epidemiologic research seeking to discriminate between adults with adult-onset vs. adolescent-onset obesity may find the CWHQ useful.     

Vertebral Strength and Estimated Fracture Risk Across the BMI Spectrum in Women

Somewhat paradoxically, fracture risk, which depends on applied loads and bone strength, is elevated in both anorexia nervosa and obesity at certain skeletal sites. Factor‐of‐risk (Φ), the ratio of applied load to bone strength, is a biomechanically based method to estimate fracture risk; theoretically, higher Φ reflects increased fracture risk. We estimated vertebral strength (linear combination of integral volumetric bone mineral density [Int.vBMD] and cross‐sectional area from quantitative computed tomography [QCT]), vertebral compressive loads, and Φ at L₄ in 176 women (65 anorexia nervosa, 45 lean controls, and 66 obese). Using biomechanical models, applied loads were estimated for: 1) standing; 2) arms flexed 90°, holding 5 kg in each hand (holding); 3) 45° trunk flexion, 5 kg in each hand (lifting); 4) 20° trunk right lateral bend, 10 kg in right hand (bending). We also investigated associations of Int.vBMD and vertebral strength with lean mass (from dual‐energy X‐ray absorptiometry [DXA]) and visceral adipose tissue (VAT, from QCT). Women with anorexia nervosa had lower, whereas obese women had similar, Int.vBMD and estimated vertebral strength compared with controls. Vertebral loads were highest in obesity and lowest in anorexia nervosa for standing, holding, and lifting (p < 0.0001) but were highest in anorexia nervosa for bending (p < 0.02). Obese women had highest Φ for standing and lifting, whereas women with anorexia nervosa had highest Φ for bending (p < 0.0001). Obese and anorexia nervosa subjects had higher Φ for holding than controls (p < 0.03). Int.vBMD and estimated vertebral strength were associated positively with lean mass (R = 0.28 to 0.45, p ≤ 0.0001) in all groups combined and negatively with VAT (R = –[0.36 to 0.38], p < 0.003) within the obese group. Therefore, women with anorexia nervosa had higher estimated vertebral fracture risk (Φ) for holding and bending because of inferior vertebral strength. Despite similar vertebral strength as controls, obese women had higher vertebral fracture risk for standing, holding, and lifting because of higher applied loads from higher body weight. Examining the load‐to‐strength ratio helps explain increased fracture risk in both low‐weight and obese women. © 2015 American Society for Bone and Mineral Research.