William M. Grove

Simultaneous Tests of Many Hypotheses in Exploratory Research

Many traditional statistical approaches to data analysis assume a relatively simple situation in which the investigator is testing a single hypothesis. Most research in psychiatry, on the other hand, is exploratory in nature and involves testing many hypotheses. Exploratory research presents special problems in data analysis, which are discussed in this overview. Special statistical approaches that are available to reduce error risk, such as the Bonferroni inequality, are described. The importance of selecting confidence levels appropriate to a particular investigation, rather than arbitrary use of the .05 level, is also discussed.

Ten-year follow-up of anorexia nervosa: clinical course and outcome

The clinical course and outcome of anorexia nervosa are presented in a 10-year follow-up study of 76 severely ill females with anorexia nervosa who met specific diagnostic criteria and had participated in a well-documented hospital treatment study. Information was obtained on 100% of the subjects. A comprehensive assessment was made in 93% of the living subjects in specific categories of weight, eating and weight control behaviours, menstrual function, anorexic attitudes, and psychological, sexual, social and vocational adjustment. Five subjects had died, which gives a crude mortality rate of 6.6%. Standardized mortality rates demonstrated an almost 13-fold increase in mortality in the anorexia nervosa subjects. Only eighteen (23.7%) were fully recovered. Sixty-four per cent developed binge-eating at some time during their illness, 57% at least weekly. Twenty-nine (41%) were still bulimic at follow-up. The high frequency and chronicity of the bulimic symptoms plus the high rate of weight relapse (42% during the first year after hospital treatment) suggest that intensive intervention is needed to help anorexics restore and maintain their weight within a normal range and to decrease abnormal eating and weight control behaviours.

Heritability of substance abuse and antisocial behavior: A study of monozygotic twins reared apart ☆

Thirty-two sets of monozygotic twins reared apart since shortly after birth (31 pairs and one set of triplets; median age at separation was 0.2 years) were interviewed separately and blindly using the Diagnostic Interview Schedule for presence of DSM-III Axis I psychiatric disorders and antisocial personality. Because the sample was recruited from a nonclinical population, predictably few subjects met criteria for such disorders. However, items counting toward diagnoses were cumulated into four scores: alcohol-related problems, drug-related problems, childhood antisocial behavior, and adult antisocial behavior. The scores showed within-scale cohesion as measured by Cronbachs coefficient alpha. The drug scale and both antisocial scales showed significant heritability (p less than 0.1), but the alcohol scale had an estimated heritability of zero (albeit with a broad confidence interval). There appeared to be substantial commonalities in the genetic factors responsible for these traits.

How does cognitive therapy work? Cognitive change and symptom change in cognitive therapy and pharmacotherapy for depression

The effects of changes in depression-relevant cognition were examined in relation to subsequent change in depressive symptoms for outpatients with major depressive disorder randomly assigned to cognitive therapy (CT; n = 32) versus those assigned to pharmacotherapy only (NoCT; n = 32). Depression severity scores were obtained at the beginning, middle, and end of the 12-week treatment period, as were scores on 4 measures of cognition: Attributional Styles Questionnaire (ASQ), Automatic Thoughts Questionnaire (ATQ), Dysfunctional Attitudes Scale (DAS), and the Hopelessness Scale (HS). Change from pretreatment to midtreatment on the ASQ, DAS, and HS predicted change in depression from midtreatment to posttreatment in the CT group, but not in the NoCT group. It is concluded that cognitive phenomena play mediational roles in cognitive therapy. However, data do not support their status as sufficient mediators.

Psychometric Detection of Schizotypy: Perceptual Aberration and Physical Anhedonia in Relatives of Schizophrenics

We administered scales of Perceptual Aberration (PERAB) and Physical Anhedonia (PHYSAN), traits that may be related to risk for schizophrenia, to 54 schizophrenics, 146 of their first-degree relatives (evaluated for schizophrenia-related disorders), and 178 normal subjects (screened for psychotic disorders in them or their relatives). For both scales, there was a significant effect of group membership. For the PERAB scale, the schizophrenics had higher scores than the normal subjects, who had higher scores than the relatives. For the PHYSAN scale, schizophrenics had higher scores than their relatives, who had higher scores than the normal subjects. Patterns of familial correlations also suggested that physical anhedonia, but not perceptual aberration, may be familial among schizophrenics and their relatives. The PHYSAN scale, but not the PERAB one, may be a useful indicator of liability for schizophrenia among the relatives of affected probands.

Smooth-pursuit eye movement dysfunction and liability for schizophrenia: implications for genetic modeling.

Forty-one nonpsychiatric subjects, 38 probands with schizophrenia, and 99 of their relatives were studied. Oculomotor functioning was bimodally distributed for probands and relatives. Oculomotor dysfunction was not present in all families with a schizophrenic proband. In those families in which it was present, there were significant phenotypic correlations between oculomotor functioning and schizophrenia-related characteristics. The patterns of familial resemblance in the families in whom oculomotor dysfunction was present were consistent with nonadditive genetic variance contributing both to oculomotor dysfunction and to the relationship between oculomotor dysfunction and clinical symptoms. These results suggest that schizophrenia may be etiologically heterogeneous and that oculomotor dysfunction may help to identify nonadditive genetic variance for this disorder.

Phase I Study of Oral CI-994 in Combination with Carboplatin and Paclitaxel in the Treatment of Patients with Advanced Solid Tumors

Purpose: To determine maximum tolerated dose of CI-994, a novel oral histone deacetylase inhibitor, in combination with carboplatin and paclitaxel in patients with advanced solid tumors. Patients and Methods: Patients with advanced solid tumors who had received two or fewer prior chemotherapy regimens were eligible for trial. Five cohorts of patients were treated with escalating doses (4–6 mg/m2) and alternative schedules (7 days or 14 days) of CI-994. Dose escalation of paclitaxel was performed to achieve tolerability of CI-994 with a paclitaxel dose of 225 mg/m2 when administered in combination with carboplatin. Pharmacokinetic assessment of CI-994 was performed by using liquid chromatography/mass spectrometry. Histone deacetylation inhibition was determined by Western blot analysis. Results: A total of 30 patients (median age 58 years) were entered into five treatment cohorts. Maximum tolerated dose of CI-994 was determined to be 4 mg/m2 administered for 7 consecutive days following paclitaxel at a dose of 225 mg/m2 and carboplatin at an area under the curve (AUC) of 6 every 21 days. Neutropenia, thrombocytopenia, and grade 3 respiratory insufficiency limited further dose escalation of CI-994. Pharmacokinetics showed that CI-994 absorption and disposition were unaffected by carboplatin and paclitaxel coadministration. Association between histone H3 acetylation levels and disease response was suggested. A subset of patients with lymphocyte H3 acetylation levels at least 1.5-fold times baseline all achieved either a clinical response or stable disease. All evaluable patients with progressive disease (PD) had H3 acetylation levels < 1.5-fold times baseline. Twenty-four of the 30 patients received greater than one cycle of treatment. Five of these patients achieved a partial response (3 nonsmall cell lung cancer, 1 colorectal cancer, and 1 unknown primary) and 2 patients achieved a complete response (esophageal and bladder cancer). Conclusion: The combination of CI-994 at a dose of 4 mg/m2 administered orally for 7 consecutive days can be safely coadministered with paclitaxel at a dose of 225 mg/m2 and carboplatin at an AUC of 6 on day 1 of a 21-day cycle. Evidence of antitumor activity is suggested and may correlate with histone modulation.

A latent trait finite mixture model for the analysis of rating agreement

This article presents a latent distribution model for the analysis of agreement on dichotomous or ordered category ratings. The model includes parameters that characterize bias, category definitions, and measurement error for each rater or test. Parameter estimates can be used to evaluate rater performance and to improve classification or measurement with use of multiple ratings. A simple maximum likelihood estimation procedure is described. Two examples illustrate the approach. Although considered in the context of analyzing rater agreement, the model provides a general approach for mixture analysis using two or more ordered-caregory measures.

The Validity of the Rorschach and the Minnesota Multiphasic Personality Inventory: Results From Meta-Analyses

Results from meta-analyses have been widely cited to defend the validity of the Rorschach. However, the meta-analyses have been flawed. For example, one meta-analysis included results that were obtained by calculating correlations but not results that were obtained by conducting t tests or analyses of variance. When we reanalyzed the data from the most widely cited meta-analysis (Parker, Hanson, & Hunsley, 1988), we found that for confirmatory studies (also called convergent-validity studies), the Minnesota Multiphasic Personality Inventory (MMPI) explained 23% to 30% of the variance, whereas the Rorschach explained only 8% to 13% of the variance. These results indicate that the Rorschach is not as valid as the MMPI.

Dissociating the long-term effects of fetal/neonatal iron deficiency on three types of learning in the rat.

Iron deficiency (ID) is a common nutrient deficiency worldwide. This condition is linked to changes in myelin formation, dopaminergic function, and energy metabolism. Early ID results in persistent long-term cognitive and behavioral disturbances in children, despite a return to normal iron status. The present study assesses formerly ID adult rats on maze learning tasks that depend on specific brain regions related to learning, specifically the hippocampus, striatum, and amygdala. Rat dams were fed ID chow starting on gestational Day 2 through postnatal Day 7, and behavioral testing began at postnatal Day 65--following a return to normal iron status. Formerly ID rats exhibited delayed acquisition of the hippocampus-dependant task and no differences from controls on the striatum- and amygdala-dependent tasks. These findings likely reflect long-term reduction in but not abolition of hippocampus-dependent learning and preserved function in other brain structures (e.g., striatum and amygdala).