Faculty Bibliography

BACKGROUND:Significant fixed effects of site (main effects of site and/or site by treatment interactions) on primary outcome have been identified in the majority of studies performed by NIDA's National Drug Abuse Treatment Clinical Trials Network. While rarely explored, identifying patient- and site-level variables that are associated with site effects can provide information about the context in which outcome is optimized. METHODS:In a 10-site clinical trial that evaluated the effectiveness of a web-based psychosocial intervention compared to usual treatment of patients (N = 507) with substance use disorders, the primary outcome analysis revealed significant main effect of site, modeled as a fixed effect, on the outcome of abstinence (Campbell et al., 2014). In the current analysis, we use a two-level, hierarchical generalized linear model (HGLM) to identify patient- and site-level variables associated with abstinence outcome, while modeling site as a random factor. RESULTS:The site-specific percentage of patients abstinent in the last 4 weeks of the study varied from 6.1% to 40%. However, only 6.7% (p = 0.08) of variability in end-of-study abstinence was accounted for by site, indicating a small-moderate effect. Among patient-level predictors, older age (OR = 1.40; 95% CI = 1.15, 1.71; p = 0.0009), abstinence at baseline (OR = 2.77; 95% CI = 1.73, 4.45; p < 0.0001), and among site-level predictors, higher annual clinic admissions (OR = 1.28; 95% CI = 1.03, 1.59; p = 0.0251) were significantly associated with increased likelihood of abstinence. When controlling for these three variables in a HGLM, only patient age and abstinence at baseline remained significant, and random factor site explained only 1.4% of variability in end-of-study abstinence, a 79% reduction in magnitude. CONCLUSIONS:The findings suggest that only some amount of variability in abstinence outcomes among sites can be explained by a combination of patient- and site-level variables. Our findings support the case that variability between sites is a natural phenomenon, and our methodological recommendation is that site be modeled as a random factor when analyzing multi-site clinical trials.

BACKGROUND:Childhood trauma is emerging as a risk factor for schizophrenia, but its mechanism with respect to etiology is unknown. One possible pathway is through leucocyte telomere length (LTL) shortening, a measure of cellular aging associated with trauma. This study examined early trauma and LTL shortening in schizophrenia and considered sex effects. METHODS:The early trauma inventory (ETI) was administered to 48 adults with DSM-5 schizophrenia and 18 comparison participants. LTL was measured using qPCR. OUTCOMES/RESULTS:Cases had significantly more global trauma (F=4.10, p<0.01) and traumatic events (F=11.23, p<0.001), but case and control groups had similar LTL (1.91±0.74 and 1.83±0.62: p=0.68). The association of early trauma and LTL differed by sex in cases and controls (Fisher's R: Z<0.05). Significant negative associations were shown in male cases and, conversely, in female controls. For example, physical punishment was associated LTL shortening in males' cases (r=-0.429, p<01). Only female controls showed significant telomere shortening in association with early trauma. INTERPRETATION/CONCLUSIONS:This data confirms the substantial excess of early trauma among schizophrenia cases. There were significant sex-differences in the relationship of the trauma to LTL, with only male cases showing the expected shortening. There were converse sex effects in the control group. Mean LTL was notably similar in cases and controls, despite the trauma-related shortening in male cases, cigarette smoking, older age and chronic illness of the cases. Factors may lengthen LTL in some schizophrenia cases. The converse sex differences in the cases are consistent with findings defective sexual differentiation in schizophrenia, consistent with other findings in the field.

BACKGROUND: Social dysfunction is common among individuals with schizophrenia. While often attributed to anhedonia, social dysfunction could also result from unrecognized anxiety. We examined the contributions of anhedonia and anxiety to social function using olfactory function to examine whether the domains had separate underpinnings. METHODS: We assessed anhedonia, anxiety and social function as well as olfactory function in well-characterized patients with schizophrenia or schizoaffective disorder and healthy controls. RESULTS: We included 56 patients and 37 controls in our study. Patients exhibited significantly higher levels of anhedonia and anxiety than controls, and the domains were highly correlated in patients. The combination of anhedonia and anxiety more strongly predicted social dysfunction than either measure alone. Smell identification was differentially related to the symptoms, with better performance predicting less anhedonia but more social fear in male patients. LIMITATIONS: The use of self-report measures precludes differentiation between recollected or recounted experience. Aside from smell identification and odour threshold, additional measures of olfaction may be considered for future studies. CONCLUSION: Anhedonia and anxiety were strongly correlated and both negatively impacted social function. The olfactory biomarker results support the conclusion that these domains are separate. Social function in patients with schizophrenia may improve with interventions for anxiety, even in the presence of marked negative symptoms.

Although "intellectual disability" has widely replaced the term "mental retardation", the debate as to whether this entity should be conceptualized as a health condition or as a disability has intensified as the revision of the World Health Organization (WHO)'s International Classification of Diseases (ICD) advances. Defining intellectual disability as a health condition is central to retaining it in ICD, with significant implications for health policy and access to health services. This paper presents the consensus reached to date by the WHO ICD Working Group on the Classification of Intellectual Disabilities. Literature reviews were conducted and a mixed qualitative approach was followed in a series of meetings to produce consensus-based recommendations combining prior expert knowledge and available evidence. The Working Group proposes replacing mental retardation with intellectual developmental disorders, defined as "a group of developmental conditions characterized by significant impairment of cognitive functions, which are associated with limitations of learning, adaptive behaviour and skills". The Working Group further advises that intellectual developmental disorders be incorporated in the larger grouping (parent category) of neurodevelopmental disorders, that current subcategories based on clinical severity (i.e., mild, moderate, severe, profound) be continued, and that problem behaviours be removed from the core classification structure of intellectual developmental disorders and instead described as associated features.

The gene Microcephalin (MCPH1) regulates brain size and has evolved under strong positive selection in the human evolutionary lineage. We show that one genetic variant of Microcephalin in modern humans, which arose approximately 37,000 years ago, increased in frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection, although the exact nature of the selection is unknown. The finding that an important brain gene has continued to evolve adaptively in anatomically modern humans suggests the ongoing evolutionary plasticity of the human brain. It also makes Microcephalin an attractive candidate locus for studying the genetics of human variation in brain-related phenotypes.