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Objective: The primary aim of this study was to assess and adjust for measurement non-equivalence (bias) by sex, race/ethnicity, and co-occurring social identities (sex x race/ethnicity) for the Marijuana Effect Expectancies Questionnaire-Brief (MEEQ-B) among Black, Latinx, and Non-Latinx white youth. The second aim was to determine how group comparisons change after accounting for possible measurement bias., Method: Black, Latinx, and Non-Latinx white youth from the Adolescent Brain and Cognitive Development Study Follow-up 3 (n=8,982; mean age=12.91; SD=0.65; 47.28% female; 15.03% Black, 22.93% Latinx, 62.04% Non-Latinx white) completed the MEEQ-B. Moderated nonlinear factor analysis (MNLFA) generated positive and negative expectancies factor scores accounting for non-equivalence. Analyses contrasted group differences by sex, race/ethnicity, and these co-occurring social identities using original (unadjusted) versus MNLFA-generated scores adjusted for measurement non-equivalence., Results: Measurement non-equivalence was observed for positive and negative expectancies across sex, race/ ethnicity and their co-occurring social identities. MNLFA revealed between-group differences at the factor and item level. Further, comparisons of original (unadjusted) and MNLFA-generated adjusted scores revealed that unadjusted scores underestimated or did not detect some group differences in positive expectancies identified using adjusted scores, and unadjusted scores underestimated how much lower negative expectancies were in Black and Latinx relative to non-Latinx white youth., Conclusions: Results highlight the need for caution when interpreting scores of a measure like the MEEQ-B that has not undergone measurement equivalence testing and demonstrate how failing to adjust for non-equivalence can result in biased estimates of positive and negative expectancies, particularly when used with diverse populations.

The common paradigm for conceptualizing the influence of genetic and environmental factors on a particular disease relies on the concept of risk. Consequently, the bulk of etiologic, including genetic, work focuses on "risk" factors. These factors are aggregated at the high end of the distribution of liability to disease, the latent variable underlying the distribution of probability and severity of a disorder. However, liability has a symmetric but distinct aspect to risk, resistance to disorder. Resistance factors, aggregated at the low end of the liability distribution and supporting health and recovery, appear to be more promising for effective prevention and intervention. Herein, we discuss existing work on resistance factors, highlighting those with known genetic influences. We examine the utility of incorporating resistance genetics in prevention and intervention trials and compare the statistical power of a series of ascertainment schemes to develop a general framework for examining resistance outcomes in genetically informative designs. We find that an approach that samples individuals discordant on measured liability, a low-risk design, is the most feasible design and yields power equivalent to or higher than commonly used designs for detecting resistance genetic and environmental effects.

Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987-2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e.g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.

Context: The detection and replication of genes involved in psychiatric outcome has been notoriously difficult. Phenotypic measurement has been offered as one explanation, although most of this discussion has focused on problems with binary diagnoses., Objective: This article focuses on two additional components of phenotypic measurement that deserve further consideration in evaluating genetic associations: (1) the measure used to reflect the outcome of interest, and (2) the developmental stage of the study population. We focus our discussion of these issues around the construct of impulsivity and externalizing disorders, and the association of these measures with a specific gene, GABRA2., Design, Setting, and Participants: Data were analyzed from the Collaborative Study on the Genetics of Alcoholism Phase IV assessment of adolescents and young adults (ages 12-26; N = 2,128)., Main Outcome Measures: Alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder symptoms were measured by psychiatric interview; Achenbach youth/adult self-report externalizing scale; Zuckerman Sensation-Seeking scale; Barratt Impulsivity scale; NEO extraversion and consciousness., Results: GABRA2 was associated with subclinical levels of externalizing behavior as measured by the Achenbach in both the adolescent and young adult samples. Contrary to previous associations in adult samples, it was not associated with clinical-level DSM symptom counts of any externalizing disorders in these younger samples. There was also association with sensation-seeking and extraversion, but only in the adolescent sample. There was no association with the Barratt impulsivity scale or conscientiousness., Conclusions: Our results suggest that the pathway by which GABRA2 initially confers risk for eventual alcohol problems begins with a predisposition to sensation-seeking early in adolescence. The findings support the heterogeneous nature of impulsivity and demonstrate that both the measure used to assess a construct of interest and the age of the participants can have profound implications for the detection of genetic associations.

In previous studies, adults with Alzheimer's disease (AD) showed memory enhancement when plasma insulin levels were raised to 85 microU/ml, whereas normal adults' memory was unchanged. Degree of memory enhancement was also related to apolipoprotein E (apoE) genotype status for AD patients. Response differences between normal and AD groups could reflect dose-response differences for insulin. To examine this question, 22 adults with AD and 15 normal adults received five doses of insulin on separate days in counterbalanced order, resulting in five plasma insulin levels (10, 25, 35, 85 and 135 microU/ml), while plasma glucose levels of ~100 mg/dl were maintained. Cognitive performance and plasma APP levels were measured after 120 min of infusion. Relative to baseline, AD patients who were not apoE- epsilon 4 homozygotes had improved memory at higher insulin levels of 35 and 85 microuU/ml, whereas normal adults and AD patients who were epsilon 4 homozygotes showed improved memory at insulin levels of 25 microU/ml. Normal adults' memory was also improved at insulin levels of 85 microU/ml. Plasma APP was lowered for adults with AD without the epsilon 4 allele at higher levels (85 microU/ml) than for normal adults and epsilon 4 homozygotes, who showed decreased APP at the 35 microU/ml level. AD patients with a single epsilon 4 allele showed a different pattern of insulin effects on APP than did other subjects. In general, few effects of insulin were seen at the highest dose for any subject group. These results support a role for insulin in normal memory and APP modulation that follows a curvilinear response pattern, and suggest that AD patients who are not epsilon 4 homozygotes have reduced sensitivity to insulin that may interfere with such modulation.

Background: Increasing plasma glucose levels improves memory in patients with Alzheimer disease (AD). Increasing plasma glucose levels also increases endogenous insulin levels, raising the question of whether memory improvement is due to changes in insulin, independent of hyperglycemia. We address this question by examining memory and counterregulatory hormone response during hyperglycemia when endogenous insulin was suppressed by concomitant infusion of the somatostatin analogue octreotide (Sandostatin)., Methods: Twenty-three patients with AD and 14 similarly aged healthy adults participated in 4 metabolic conditions on separate days: (1) hyperinsulinemia (538 pmol/L) with fasting glucose (5.6 mmol/L [100 mg/dL]), achieved by insulin and variable dextrose infusion; (2) hyperglycemia (12.5 mmol/L [225 mg/dL]) with fasting insulin (57 pmol/L), achieved by dextrose and somatostatin (octreotide) infusion (150 mg/h); (3) placebo with isotonic sodium chloride solution (saline) infusion (fasting insulin and glucose); and (4) an active control condition in which somatostatin alone was infused (150 mg/h). Declarative memory (story recall) and selective attention (Stroop interference test) were measured during steady metabolic states., Results: Patients with AD showed improved memory during hyperinsulinemia relative to placebo (P = .05) and relative to hyperglycemia (P<.005). Memory did not improve during hyperglycemia when insulin was suppressed. Somatostatin analogue infusion alone also improved memory for patients with AD (P<.05). Hyperinsulinemia increased cortisol levels in subjects with AD, whereas somatostatin alone lowered cortisol concentrations., Conclusions: These results confirm that elevated insulin without hyperglycemia enhances memory in adults with AD, and indicate that insulin is essential for hyperglycemic memory facilitation. These results also suggest a potential therapeutic role for somatostatin in AD.

Higher fasting plasma insulin levels and reduced CSF-to-plasma insulin ratios, suggestive of insulin resistance, have been observed in patients with Alzheimer's disease (AD) who do not possess an apolipoprotein E (APOE)-epsilon4 allele. We examined the relationship of APOE and gender to peripheral insulin action and hyperinsulinemic memory facilitation in patients with AD using a sensitive measure of insulin-mediated glucose disposal. Participants were 32 patients with AD (9 without an epsilon4 allele, 23 with an epsilon4 allele) and 25 healthy age-matched adults (16 without an epsilon4 allele, 9 with an epsilon4 allele). AD subjects without an epsilon4 allele had significantly lower insulin-mediated glucose disposal rates than AD patients with an epsilon4 allele (p < 0.03), or than normal adults without an epsilon4 allele (p < 0.02). Female AD subjects showed lower insulin-mediated glucose disposal rates than did male AD subjects (p < 0.02). No significant interaction was observed between APOE group and gender, suggesting that these effects are independent. AD subjects without an epsilon4 allele also showed significant memory facilitation in the hyperinsulinemic condition (p < 0.04), whereas the AD-epsilon4 group did not. Also in the hyperinsulinemic condition, AD patients without an epsilon4 allele had lower insulin levels than patients with an epsilon4 allele (p < 0.02), and women with AD had lower insulin levels than did men with AD despite similar insulin infusion rates and body mass (p < 0.004). No gender or genotype effects were observed in either condition for normal subjects. These results provide in vivo evidence of differences in insulin-mediated energy metabolism between epsilon4 and non-epsilon4 AD, and suggest that defective insulin action may be of particular pathophysiologic significance for patients without an epsilon-4 allele.