Stephen J. Finch

Power and sample size calculations for case-control genetic association tests when errors are present: application to single nucleotide polymorphisms.

The purpose of this work is to quantify the effects that errors in genotyping have on power and the sample size necessary to maintain constant asymptotic Type I and Type II error rates (SSN) for case-control genetic association studies between a disease phenotype and a di-allelic marker locus, for example a single nucleotide polymorphism (SNP) locus. We consider the effects of three published models of genotyping errors on the chi-square test for independence in the 2 × 3 table. After specifying genotype frequencies for the marker locus conditional on disease status and error model in both a genetic model-based and a genetic model-free framework, we compute the asymptotic power to detect association through specification of the test’s non-centrality parameter. This parameter determines the functional dependence of SSN on the genotyping error rates. Additionally, we study the dependence of SSN on linkage disequilibrium (LD), marker allele frequencies, and genotyping error rates for a dominant disease model. Increased genotyping error rate requires a larger SSN. Every 1% increase in sum of genotyping error rates requires that both case and control SSN be increased by 2–8%, with the extent of increase dependent upon the error model. For the dominant disease model, SSN is a nonlinear function of LD and genotyping error rate, with greater SSN for lower LD and higher genotyping error rate. The combination of lower LD and higher genotyping error rates requires a larger SSN than the sum of the SSN for the lower LD and for the higher genotyping error rate.

Young Adult Drug Use and Delinquency: Childhood Antecedents and Adolescent Mediators

OBJECTIVE The aims of this study were (1) to examine the childhood, early adolescent, and late adolescent predictors of young adult drug use and delinquency; and (2) to explore the effects of drug use on delinquent behavior. METHOD Data were gathered during the course of a 20-year longitudinal study of children representative of the Northeast. Data were gathered on childhood aggression, early and late adolescent drug use and delinquency, and young adult drug use and delinquency. RESULTS Overall, the results were consistent with our proposed model. Childhood aggression had an adverse effect on young adult drug use and female deviant behavior. Drug use and delinquency during early and late adolescence served as the mediator between childhood aggression and young adult drug use. Moreover, adolescent drug use was associated with later delinquency. CONCLUSIONS The findings indicated that childhood aggression was related to both young adult drug use and delinquency. Second, there was stability of drug use and delinquency between early adolescence and young adulthood. Third, drug use during early adolescence had an impact on delinquency not only in early adolescence, but also in late adolescence and young adulthood.

Factors affecting statistical power in the detection of genetic association

The mapping of disease genes to specific loci has received a great deal of attention in the last decade, and many advances in therapeutics have resulted. Here we review family-based and population-based methods for association analysis. We define the factors that determine statistical power and show how study design and analysis should be designed to maximize the probability of localizing disease genes.

Simulated percentage points for the null distribution of the likelihood ratio test for a mixture of two normals

We find the percentage points of the likelihood ratio test of the null hypothesis that a sample of n observations is from a normal distribution with unknown mean and variance against the alternative that the sample is from a mixture of two distinct normal distributions, each with unknown mean and unknown (but equal) variance. The mixing proportion pi is also unknown under the alternative hypothesis. For 2,500 samples of sizes n = 15, 20, 25, 40, 50, 70, 75, 80, 100, 150, 250, 500, and 1,000, we calculated the likelihood ratio statistic, and from these values estimated the percentage points of the null distributions. Our algorithm for the calculation of the maximum likelihood estimates of the unknown parameters included precautions against convergence of the maximization algorithm to a local rather than global maximum. Investigations for convergence to an asymptotic distribution indicated that convergence was very slow and that stability was not apparent for samples as large as 1,000. Comparisons of the percentage points to the commonly assumed chi-squared distribution with 2 degrees of freedom indicated that this assumption is too liberal; i.e., ones P-value is greater than that indicated by chi 2(2). We conclude then that one would need what is usually an unfeasibly large sample size (n greater than 1,000) for the use of large-sample approximations to be justified.

Power and sample size calculations in the presence of phenotype errors for case/control genetic association studies

BackgroundPhenotype error causes reduction in power to detect genetic association. We present a quantification of phenotype error, also known as diagnostic error, on power and sample size calculations for case-control genetic association studies between a marker locus and a disease phenotype. We consider the classic Pearson chi-square test for independence as our test of genetic association. To determine asymptotic power analytically, we compute the distributions non-centrality parameter, which is a function of the case and control sample sizes, genotype frequencies, disease prevalence, and phenotype misclassification probabilities. We derive the non-centrality parameter in the presence of phenotype errors and equivalent formulas for misclassification cost (the percentage increase in minimum sample size needed to maintain constant asymptotic power at a fixed significance level for each percentage increase in a given misclassification parameter). We use a linear Taylor Series approximation for the cost of phenotype misclassification to determine lower bounds for the relative costs of misclassifying a true affected (respectively, unaffected) as a control (respectively, case). Power is verified by computer simulation.ResultsOur major findings are that: (i) the median absolute difference between analytic power with our method and simulation power was 0.001 and the absolute difference was no larger than 0.011; (ii) as the disease prevalence approaches 0, the cost of misclassifying a unaffected as a case becomes infinitely large while the cost of misclassifying an affected as a control approaches 0.ConclusionOur work enables researchers to specifically quantify power loss and minimum sample size requirements in the presence of phenotype errors, thereby allowing for more realistic study design. For most diseases of current interest, verifying that cases are correctly classified is of paramount importance.

Developmental trajectories of cigarette smoking from adolescence to the early thirties : Personality and behavioral risk factors

The purpose of this study was to identify distinct trajectories of cigarette smoking from ages 14 to 32, and to examine adolescent personality factors that distinguish trajectories of smoking behavior. Participants (N = 975) were randomly selected and followed prospectively since 1975. Follow-up data on cigarette use and personality and behavioral attributes were collected at five points in time, using structured interviews given in private by trained interviewers. Of these subjects, 746 comprised the cohort used in this study. Growth mixture modeling identified five smoking trajectory groups: nonsmokers, occasional smokers, late starters, quitters, and heavy/continuous smokers. Adolescent personality and behavioral risk factors such as lower ego integration, more externalizing behavior, and lower educational aspirations distinguished the trajectory groups. No gender differences were noted. The findings supported the hypotheses indicating multiple distinct trajectory groups of smoking behavior. Smoking behavior appeared in early adolescence and most often continued into adulthood. Emotional difficulties (i.e., lower ego integration), externalizing behavior, and lower educational aspirations in early adolescence were associated both with smoking at an early age and with continuing to smoke into the thirties. To be more effective, smoking prevention programs should target personality and behavioral variations before smoking becomes habitual, particularly focused on characteristics reflecting behavioral problems as manifested in emotional difficulties, externalizing behavior, and low educational aspirations in early adolescence. The implications for research, prevention, and treatment are discussed.

Prenatal ‘female hormone’ administration and psychosexual development in human males

Abstract (1) Considerable data exist from animal research relating prenatal hormone levels to postnatal behaviors in the male. The data from human males are few. One strategy for testing this association is the study of humans exposed prenatally to exogenous ‘pregnancy maintaining hormones’. (2) Fifty-eight young adult males exposed to one of four hormone regimens were matched against nonhormone exposed controls. There were 17 males exposed to diethylstilbestrol (DES), 22 exposed to DES and natural progesterone, 10 to natural progesterone only, and 13 to synthetic progesterone. (3) Subjects were interviewed for various aspects of psychosexual development, and administered the Bem Sex-Role Inventory (BSRI), the Guilford-Zimmerman Temperament Survey (GZTS), the Strong Vocational Interest Blank (SVIB), and the Embedded Figures Test (EFT). (4) Drug, total dosage, and time of drug administration were significantly associated with several aspects of boyhood, adolescent, and adult psychosexual development on interview and with differences in scales of the psychometric tests. (5) The most contrasting boyhood behaviors were between those exposed to progesterone and DES. Progesterone subjects tended to recall boyhood behaviors which departed from the conventional male mode toward ‘femininity’. The DES subjects tended to recall the most conventionally ‘masculine’ boyhoods. During adulthood, DES plus natural progesterone subjects reported a high sex drive while synthetic progesterone subjects reported a low sex drive. Erectile failure was more often reported by subjects exposed to natural progesterone only. (6) Three drug regimens were associated with elevations of the Feminine scale of the BSRI and two with elevations of the feminine scale of the GZTS. (7) The rates of homosexual behavior were comparable for drug and non-drug-exposed subjects.

Aggression, intrapsychic distress, and drug use : antecedent and intervening processes

OBJECTIVE To explore the interrelation of childhood aggression, early and late adolescent intrapsychic distress, unconventionality, and drug use. METHOD Data were obtained from the subjects when they were 5 to 10 years old. Follow-up interviews were conducted when the subjects were between 13 and 18 years old and again when they were 15 to 20 years old. RESULTS A LISREL analysis indicated that childhood aggression was related to later intrapsychic distress, unconventionality, and drug use. There were significant pathways from childhood aggression to drug use at 15 to 20 years of age, with mediation through intrapsychic distress and unconventionality, and during adolescence there was a pathway from intrapsychic distress to unconventionality, leading to legal and subsequently illegal drug use. There was also considerable stability in intrapsychic distress, unconventionality, and drug use. CONCLUSION Intrapsychic distress and unconventionality are important mediators of childhood aggression and adult drug use.

The likelihood ratio test for the two-component normal mixture problem : power and sample size analysis

We find, through simulation and modeling, an approximation to the alternative distribution of the likelihood ratio test for two-component mixtures in which the components have different means but equal variances. We consider the range of mixing proportions from 0.5 through .95. Our simulation results indicate a dependence of power on the mixing proportion when pi less than .2 and pi greater than .80. Our model results indicated that the alternative distribution is approximately noncentral chi-square, possibly with 2 degrees of freedom. Using this model, we estimate a sample of 40 is needed to have 50% power to detect a difference between means equal to 3.0 for mixing proportions between .2 and .8. The sample size increases to 50 when the mixing proportion is .90 (or .1) and 82 when the mixing proportion is .95 (or .05). This paper contains a complete table of sample sizes needed for 50%, 80%, and 90% power.

Adolescent ADHD and Adult Physical and Mental Health, Work Performance, and Financial Stress

OBJECTIVE: There is a scarcity of longitudinal studies of adolescents with attention-deficit/hyperactivity disorder (ADHD) followed until adulthood. We studied the relationship between ADHD in adolescence and impaired general physical health, impaired general mental health, antisocial personality disorder, impaired work performance, and high financial stress in adulthood. METHODS: A prospective design incorporated 6 assessments of participants spanning mean ages from 14 to 37 years. Two baseline assessments were taken between ages 14 and 16 years, and 5 outcome assessments were taken at mean age 37 years. Participants were assessed with structured interviews and questionnaires. The participants were from a community sample of individuals initially drawn in 1975 and followed to a mean age of 37 years in 2009. RESULTS: The adjusted odds ratios and 95% confidence intervals (CIs) for ADHD in adolescence as related to internal stress in adulthood were 1.82 (95% CI = 1.01–3.25; P < .05) for impaired general physical health, 2.36 (95% CI = 1.23–4.51; P < .01) for impaired general mental health, and 3.28 (95% CI = 1.51–7.13; P < .01) for antisocial personality disorder. The adjusted odds ratios and 95% CIs for ADHD in adolescence as related to external stress were 2.46 (95% CI = 1.37–4.43; P < .01) for impaired work performance and 3.33 (95% CI = 1.70–6.55; P < .001) for high financial stress. CONCLUSIONS: Clinicians should focus on early diagnosis and treatment of adolescent ADHD because it is a major predictor of an array of physical, mental, work, and financial problems in adulthood.