Marcus R. Munafò

Power failure: why small sample size undermines the reliability of neuroscience

A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles.

Serotonin Transporter (5-HTTLPR) Genotype and Amygdala Activation: A Meta-Analysis

BACKGROUND We evaluated the magnitude of the reported associations between amygdala activation and the serotonin transporter gene linked polymorphic region (5-HTTLPR) and the likely effect size of this relationship. METHODS We used meta-analytic techniques to combine data from existing published and unpublished studies. We also tested for possible publication bias and explored possible moderating influences on any association, such as sample ancestry. RESULTS Our results provide support for the association of the 5-HTTLPR polymorphism and amygdala activation and suggest that this locus may account for up to 10% of phenotypic variance. Although we did not observe evidence for potential publication bias in our main analysis, this was due in part to efforts to obtain unpublished data pertinent to this meta-analysis, and when three unpublished data sets were excluded we did observe evidence of such bias. We also observed evidence that the first published study may provide an overestimate of the true effect size, which is consistent with findings from genetic association studies of other phenotypes. CONCLUSIONS Although our analysis provides support for the association of the 5-HTTLPR polymorphism and amygdala activation, it also suggests that most studies to date are nevertheless lacking in statistical power. Increasing the sample sizes of future imaging genetics studies will allow a more accurate characterization of any true effect size and afford adequate power to examine the impact of multiple polymorphisms that likely work in concert to affect gene function and, in turn, bias neural processes mediating dispositional traits such as temperament and personality.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Socioeconomic status and smoking: A review

Smoking prevalence is higher among disadvantaged groups, and disadvantaged smokers may face higher exposure to tobaccos harms. Uptake may also be higher among those with low socioeconomic status (SES), and quit attempts are less likely to be successful. Studies have suggested that this may be the result of reduced social support for quitting, low motivation to quit, stronger addiction to tobacco, increased likelihood of not completing courses of pharmacotherapy or behavioral support sessions, psychological differences such as lack of self‐efficacy, and tobacco industry marketing. Evidence of interventions that work among lower socioeconomic groups is sparse. Raising the price of tobacco products appears to be the tobacco control intervention with the most potential to reduce health inequalities from tobacco. Targeted cessation programs and mass media interventions can also contribute to reducing inequalities. To tackle the high prevalence of smoking among disadvantaged groups, a combination of tobacco control measures is required, and these should be delivered in conjunction with wider attempts to address inequalities in health.

Gene × Environment Interactions at the Serotonin Transporter Locus

BACKGROUND Although it is universally accepted that human disease and behavior depend upon both environmental and genetic variation, a view supported by family and twin studies, examples of environmental interactions with genes identified at the molecular level (G x E) are not so well established. METHODS We carried out a systematic review and meta-analysis of the serotonin transporter (5-HTTLPR) polymorphic region x stressful life event (SLE) literature and investigated to what extent the main effects reported in this literature are consistent with a number of G x E hypotheses. Our aim was to provide a framework in which to assess the robustness of the claim for the presence of an interaction. RESULTS The results from our systematic review and meta-analysis indicate that the main effect of 5-HTTLPR genotype and the interaction effect between 5-HTTLPR and SLE on risk of depression are negligible. We found that only a minority of studies report a replication that is qualitatively comparable to that in the original report. CONCLUSIONS Given reasonable assumptions regarding likely genetic and environmental effect sizes, our simulations indicate that published studies are underpowered. This, together with other aspects of the literature, leads us to suggest that the positive results for the 5-HTTLPR x SLE interactions in logistic regression models are compatible with chance findings.

Structural Neuroimaging Studies in Major Depressive Disorder: Meta-analysis and Comparison With Bipolar Disorder

CONTEXT Although differences in clinical characteristics exist between major depressive disorder (MDD) and bipolar disorder (BD), consistent structural brain abnormalities that distinguish the disorders have not been identified. OBJECTIVES To investigate structural brain changes in MDD using meta-analysis of primary studies; assess the effects of medication, demographic, and clinical variables; and compare the findings with those of a meta-analysis of studies on BD. DATA SOURCES The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1980, to February 2, 2010. STUDY SELECTION Two hundred twenty-five studies that used magnetic resonance imaging or x-ray computed tomography to compare brain structure in patients with MDD with that of controls were included in an online database, and 143 that measured common brain structures were selected for meta-analysis. DATA EXTRACTION Twenty-five variables, including demographic and clinical data, were extracted from each study, when available. For the meta-analysis, mean structure size and standard deviation were extracted for continuous variables, and the proportion of patients and controls with an abnormality in brain structure was extracted for categorical variables. DATA SYNTHESIS Compared with the structure of a healthy brain, MDD was associated with lateral ventricle enlargement; larger cerebrospinal fluid volume; and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal lobe, orbitofrontal cortex, and gyrus rectus. Patients during depressive episodes had significantly smaller hippocampal volume than patients during remission. Compared with BD patients, those with MDD had reduced rates of deep white matter hyperintensities, increased corpus callosum cross-sectional area, and smaller hippocampus and basal ganglia. Both disorders were associated with increased lateral ventricle volume and increased rates of subcortical gray matter hyperintensities compared with healthy controls. CONCLUSIONS The meta-analyses revealed structural brain abnormalities in MDD that are distinct from those observed in BD. These findings may aid investigators attempting to discriminate mood disorders using structural magnetic resonance imaging data.

Delayed reward discounting and addictive behavior: a meta-analysis

RationaleDelayed reward discounting (DRD) is a behavioral economic index of impulsivity and numerous studies have examined DRD in relation to addictive behavior. To synthesize the findings across the literature, the current review is a meta-analysis of studies comparing DRD between criterion groups exhibiting addictive behavior and control groups.ObjectivesThe meta-analysis sought to characterize the overall patterns of findings, systematic variability by sample and study type, and possible small study (publication) bias.MethodsLiterature reviews identified 310 candidate articles from which 46 studies reporting 64 comparisons were identified (total N = 56,013).ResultsFrom the total comparisons identified, a small magnitude effect was evident (d = .15; p < .00001) with very high heterogeneity of effect size. Based on systematic observed differences, large studies assessing DRD with a small number of self-report items were removed and an analysis of 57 comparisons (n = 3,329) using equivalent methods and exhibiting acceptable heterogeneity revealed a medium magnitude effect (d = .58; p < .00001). Further analyses revealed significantly larger effect sizes for studies using clinical samples (d = .61) compared with studies using nonclinical samples (d = .45). Indices of small study bias among the various comparisons suggested varying levels of influence by unpublished findings, ranging from minimal to moderate.ConclusionsThese results provide strong evidence of greater DRD in individuals exhibiting addictive behavior in general and particularly in individuals who meet criteria for an addictive disorder. Implications for the assessment of DRD and research priorities are discussed.

The endophenotype concept in psychiatric genetics

The idea that some phenotypes bear a closer relationship to the biological processes that give rise to psychiatric illness than diagnostic categories has attracted considerable interest. Much effort has been devoted to finding such endophenotypes, partly because it is believed that the genetic basis of endophenotypes will be easier to analyse than that of psychiatric disease. This belief depends in part on the assumption that the effect sizes of genetic loci contributing to endophenotypes are larger than those contributing to disease susceptibility, hence increasing the chance that genetic linkage and association tests will detect them. We examine this assumption by applying meta-analytical techniques to genetic association studies of endophenotypes. We find that the genetic effect sizes of the loci examined to date are no larger than those reported for other phenotypes. A review of the genetic architecture of traits in model organisms also provides no support for the view that the effect sizes of loci contributing to phenotypes closer to the biological basis of disease is any larger than those contributing to disease itself. While endophenotype measures may afford greater reliability, it should not be assumed that they will also demonstrate simpler genetic architecture.

A Meta-Analytic Investigation of the Relationship between Attentional Bias and Subjective Craving in Substance Abuse.

Theoretical models of addiction suggest that attentional bias for substance-related cues should be associated with self-reported craving. The authors evaluated the strength of the association by performing a meta-analysis on 68 independent data sets from which correlation coefficients between subjective craving and attentional bias indices were derived. Additional stratified analyses were conducted to identify any variables that might moderate the association between craving and attentional bias. The primary meta-analysis indicated a significant, albeit weak (r=.19), association between attentional bias and craving. Stratified analyses revealed that the association was larger for illicit drug and caffeine craving than for alcohol and tobacco craving, larger for direct measures of attention (eye movement measures and event-related potential measures) than for indirect behavioral measures of attentional bias, and larger when craving strength was high than when it was low (all ps<.05). The size of the correlation did not differ among patients in treatment and individuals who were not seeking treatment. These results suggest that attentional bias and craving are related phenomena, although the relationship is generally modest and appears to be moderated by various factors. Theoretical implications are discussed.

Meta-Analysis of the Cognitive Effects of the Catechol-O-Methyltransferase Gene Val158/108Met Polymorphism

BACKGROUND Cognitive endophenotypes may further our understanding of the genetic basis of psychiatric disorders, and the catechol-O-methyltransferase (COMT) gene is a promising candidate gene for both cognitive function and disorder. We conducted a meta-analysis of reported associations between the COMT Val158/108Met polymorphism and measures of memory and executive function. METHODS The PubMed database was searched for studies relating cognitive functions and the COMT Val158/108Met polymorphism. This enabled meta-analyses of six cognitive phenotypes (Trail Making task, verbal recall, verbal fluency, IQ score, n-back task, and Wisconsin Card Sorting Test). Data were extracted by two reviewers and included cognitive scores by COMT genotype, publication year, diagnostic status, ancestry, proportion of male participants, and whether genotype frequencies were consistent with Hardy-Weinberg equilibrium. RESULTS We found no association between COMT genotype and the majority of phenotypes. There was evidence of association with IQ score (d = .06), which did not differ significantly by ancestry, sex, average sample age, or patient status. For the n-back task, there was no robust evidence for genetic association, but the effect size was significantly larger in patient (d = .40) than nonpatient (d = -.27) populations, larger in both samples with fewer male subjects, and those of greater average age. There was also evidence of publication bias and decreasing effect sizes with later publication. CONCLUSIONS Despite initially promising results, the COMT Val158/108Met polymorphism appears to have little if any association with cognitive function. Publication bias may hamper attempts to understand the genetic basis of psychological functions and psychiatric disorders.