Nancy R. Mendell

Microduplications of 16p11.2 are associated with schizophrenia.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 × 10−5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 × 10−7), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10−7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10−13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

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.

Antisaccade performance is abnormal in schizophrenia patients but not in their biological relatives

Numerous studies have replicated the finding that schizophrenia patients make an increased number of errors on an antisaccade task. Some studies have reported that relatives of schizophrenia patients also make an increased number of antisaccade errors, a finding that has been interpreted to support the usefulness of compromised antisaccade performance as an index of genetic liability for schizophrenia. We examined performance on an antisaccade task in schizophrenia patients, nonpsychiatric controls, first-degree relatives of schizophrenia patients and first-degree relatives of nonpsychiatric controls. Schizophrenia patients made significantly more errors than did nonpsychiatric controls, but relatives of schizophrenia patients did not differ from relatives of controls or from all controls. Increased antisaccade errors on the standard version of the antisaccade task are associated with schizophrenia, but do not seem to be a co-familial trait for schizophrenia.

Effects of Methylphenidate Dosage in Hyperactive Reading-disabled Children: II. Reading Achievement

ABSTRACT Effects of methylphenidate (MP) on reading achievement in 7- to 13-year-old children with hyperactivity and reading disorder were investigated. Forty-two children were assigned to one of four MP dose groups (placebo, 0.3 mg/kg, 0.5 mg/kg, and 0.7 mg/kg). Behavior ratings and academic achievement scores were obtained at the beginning of the study, after 12 weekly reading sessions, and again after 12 additional weekly reading sessions. Results showed positive effects of MP on reading that were mediated through behavioral control (i.e., achievement was significantly related to behavioral response to MP treatment), especially during the first 3 months of treatment. A specific effect of MP on word recognition involving verbal retrieval, as opposed to phonic skills, was also found. Implications for clinical treatment are discussed, and questions regarding the interaction of drug dose, behavioral response, and academic learning are posed.

RELATIONSHIP OF JOB STRAIN TO STANDARD CORONARY RISK FACTORS AND PSYCHOLOGICAL CHARACTERISTICS IN WOMEN AND MEN OF THE FAMILY HEART STUDY

This study reports on standard coronary risk factors (plasma lipids and lipoproteins, blood pressure, heart rate, age, body mass index) and psychosocial variables (job strain, Type A behavior, hostility, illnesses, medical and psychological symptoms, health-damaging behavior) in a community sample of 324 employed men, 203 employed women, and 155 female homemakers. Employed women reported less hostility and fewer illnesses than homemakers and had lower cholesterol levels than homemakers and men. Job characteristics were unrelated to standard coronary risk factor levels in both sexes, but predicted medical symptoms and health-damaging behavior in men. These findings suggest that employment is associated with enhanced medical and physical well-being among women and point to possible behavioral and psychological pathways by which job strain may adversely influence mens health.

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.

Probabilistic Measures of Adequacy of a Numerical Search for a Global Maximum

Abstract Measures of the probability of all unobserved species are applied to the problem of assessing the adequacy of a search for a global maximum using random starting points. The measures, as used here, estimate the probability that an iterative algorithm using a randomly selected starting point will find a solution not observed in previous random starting points. The probability of an unobserved global maximum is less than or equal to this probability. We used these measures to evaluate the adequacy of our search procedure for the maximum likelihood estimates of the parameters of a mixture of two normals. These measures indicated that for most problems generated there was little chance that there were unobserved domains of convergence. Occasional problems, however, had appreciable estimated probabilities. In such problems, examination of the data suggested regions where a more focused search for unobserved domains of convergence was warranted.

Effects of methylphenidate dosage in hyperactive reading-disabled children: I. Behavior and cognitive performance effects.

ABSTRACT Forty-seven children diagnosed as having Attention Deficit Disorder with Hyperactivity and Developmental Reading Disorder were randomly assigned to receive placebo or one of three methylphenidate dosages (0.3, 0.5, 0.7 mg/kg) twice daily for 6 months, and measurements of social behavior, short-term memory, associative learning, and methylphenidate plasma concentration were obtained at scheduled intervals. Teachers and parents rated hyperactive behaviors as significantly reduced in the 0.7 mg/kg dose group as compared with the placebo group. Where drug effects were obtained on the short-term memory and associative learning tasks, these also resulted in significantly improved performance in the 0.7 mg/kg dose group. Teachers perceived an increase in hyperactivity during the last 3 months of treatment, and this was not explained by changes in methylphenidate plasma concentration. Possible explanations for this unexpected finding in terms of situational factors and drug tolerance are discussed.

Antisaccade performance in biological relatives of schizophrenia patients: a meta-analysis

Poor performance on the antisaccade (AS) task has been interpreted as a potential indicator of genetic liability that may enhance the power of linkage studies of a multidimensional phenotype for schizophrenia. Every study has replicated the finding of significantly worse performance in schizophrenia patients regardless of which specific antisaccade paradigm was employed. In some studies involving a standard version of the antisaccade task, relatives of schizophrenia patients made an increased number of errors, but in other studies that used this same paradigm, relatives of schizophrenia patients did not differ from controls. In this paper, we report the results of a meta-analysis on studies that used the standard antisaccade paradigm. The meta-analysis shows that those studies that reported large effect sizes and statistically significant differences between relatives of schizophrenia patients and controls used inclusion/exclusion criteria that were not symmetrical between the two groups, whereas those studies that reported small and nonsignificant differences between relatives of schizophrenia patients and controls used symmetrical inclusion/exclusion criteria. Specifically, studies that applied stricter psychopathology exclusion criteria to controls than to relatives of schizophrenia patients had larger effect sizes than studies that applied comparable exclusion criteria to both groups, suggesting that antisaccade performance is compromised by psychopathology in general rather than by schizophrenia per se. Since symmetrical inclusion/exclusion criteria between relatives of schizophrenia patients and controls are essential for a genetic analysis, and those studies that did apply symmetrical criteria had small effect sizes, the available data suggest that poor antisaccade performance is unlikely to be useful in identifying clinically unaffected carriers of genes for schizophrenia.

Methylphenidate increases thought disorder in recent onset schizophrenics, but not in normal controls

The effects of apomorphine and methylphenidate on thought disorder, as measured by the Thought Disorder Index, in schizophrenic patients and in normal controls were evaluated. Methylphenidate, but not apomorphine, increased thought disorder in patients. Neither drug significantly increased thought disorder in controls.