342 research outputs found
Combining isotonic regression and EM algorithm to predict genetic risk under monotonicity constraint
In certain genetic studies, clinicians and genetic counselors are interested
in estimating the cumulative risk of a disease for individuals with and without
a rare deleterious mutation. Estimating the cumulative risk is difficult,
however, when the estimates are based on family history data. Often, the
genetic mutation status in many family members is unknown; instead, only
estimated probabilities of a patient having a certain mutation status are
available. Also, ages of disease-onset are subject to right censoring. Existing
methods to estimate the cumulative risk using such family-based data only
provide estimation at individual time points, and are not guaranteed to be
monotonic or nonnegative. In this paper, we develop a novel method that
combines Expectation-Maximization and isotonic regression to estimate the
cumulative risk across the entire support. Our estimator is monotonic,
satisfies self-consistent estimating equations and has high power in detecting
differences between the cumulative risks of different populations. Application
of our estimator to a Parkinson's disease (PD) study provides the age-at-onset
distribution of PD in PARK2 mutation carriers and noncarriers, and reveals a
significant difference between the distribution in compound heterozygous
carriers compared to noncarriers, but not between heterozygous carriers and
noncarriers.Comment: Published in at http://dx.doi.org/10.1214/14-AOAS730 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
Recommended from our members
Neuropsychological Detection and Characterization of Preclinical Alzheimer's Disease
We attempted to characterize the changes in cognition associated with the earliest, or preclinical, stages of Alzheimer's disease (AD) by administering a comprehensive neuropsychological test battery to a group of initially nondemented older adults participating in a prospective epidemiologic study of dementia. Using Cox regression analyses, we examined the associations between baseline neuropsychological test scores and subsequent development of AD. Results confirmed preliminary findings that baseline scores on the Boston Naming Test, Immediate Recall on the Selective Reminding Test, and the Similarities subtest of the Wechsler Adult Intelligence Scale-Revised were significantly and independently associated with later diagnosis of AD. Analyses controlled for the effects of age, education, sex, and language of test administration. These results lend support to the notion of a preclinical phase of AD and indicate that this very early stage of AD is characterized by poor word-finding ability, abstract reasoning, and memory
Recommended from our members
Interrater Reliability of Extrapyramidal Signs in a Group Assessed for Dementia
Extrapyramidal signs were rated by three neurologists in 20 patients who had either been diagnosed as having probable Alzheimer's disease or who were being evaluated for dementia. In general, good inter-rater reliability was found for the presence or absence of extrapyramidal signs, although agreement over the presence of some signs was reduced when distinctions between normality and slight departures from normality were required
Recommended from our members
Safety and Efficacy of Oral Physostigmine in the Treatment of Alzheimer Disease
Results of therapeutic trials with physostigmine in the treatment of Alzheimer disease (AD) have been inconsistent and controversy persists concerning safety and efficacy. In a double-blind, placebo-controlled, crossover study, patients received 6 weeks of oral physostigmine (OP) and placebo in random order. Twenty-nine patients with AD received as much as 16 mg/day of OP and were assessed with neuropsychological and functional measures. No significant cardiac side effects were noted, though other systemic adverse effects were noted, requiring dose reduction in four patients. There was a slight but significant improvement (12%) in performance on the selective reminding test with physostigmine and the memory performance was correlated with dosage. This improvement compares favorably with the 15% decrease in scores seen in an untreated comparison cohort followed for an equivalent time period. There was a trend toward an improvement in communication and a reduction in memory complaint. These results suggest that oral physostigmine is safe and may improve memory in AD
Recommended from our members
The roles of family members, health care workers, and others in decision-making processes about genetic testing among individuals at risk for Huntington disease
Purpose: To understand how individuals at risk for Huntington disease view the roles of others, e.g., family members and health care workers, in decision making about genetic testing.
Methods: Twenty-one individuals (eight mutation-positive, four mutation-negative, and nine not tested) were interviewed for approximately 2 hours each.
Results: Interviewees illuminated several key aspects of the roles of family members and health care workers (in genetics and other fields) in decision making about testing that have been underexplored. Family members often felt strongly about whether an individual should get tested. Health care workers provided information and assistance with decision making and mental health referrals that were often helpful. Yet health care workers varied in knowledge and sensitivity regarding testing issues, and the quality of counseling and testing experiences can range widely. At times, health care workers without specialized knowledge of Huntington disease offered opinions of whether to test. Input from families and health care workers could also conflict with each other and with an individual's own preferences. Larger institutional and geographic contexts shaped decisions as well.
Conclusion: Decision-making theories applied to Huntington disease testing have frequently drawn on psychological models, yet the current data highlight the importance of social contexts and relationships in testing decisions. This report, the first to our knowledge to explore individuals' perceptions of social factors (particularly family and health care worker involvement) in Huntington disease testing decisions, has critical implications for practice, education, research, and policy
Recommended from our members
An Estimate of the Incidence of Depression in Idiopathic Parkinson's Disease
Estimates of the prevalence of depression in idiopathic Parkinson's disease vary, but have been greater than in most comparison groups. In a survey of patients with Parkinson's disease (N = 339), the prevalence of depression was 47%. A total of 326 cases were reviewed to estimate the incidence of depression from September 30, 1984, to July 31,1989. Assessments of depression during both the prevalent and the incident periods were noted in 258 cases. There was no history of depression in 129 cases, and nine new cases occurred. The incidence rate was 1.86% per year and the cumulative risk was 8.6%. Published estimates of the incidence of depression in the general population are few. In one study, the annual incidence of depression in individuals older than 40 years was 0.17%. In another, the incidence of depression in individuals older than 50 years was 0.14% for men and 0.29% for women. Although our retrospective study probably underdiagnoses depression, the incidence of depression is increased in Parkinson's disease
Recommended from our members
Neuropsychologic Impairment in Early HIV Infection: A Risk Factor for Work Disability
Objective: To explore the functional significance of incident neuropsychologic impairment among initially asymptomatic subjects infected with human immunodeficiency virus. Design: Prospective, observational cohort study of homosexual and bisexual men to examine the incidence of work disability related to the onset of neuropsychologic impairment. Setting: A university clinical and behavioral research site in New York City. Participants: Sample of 207 homosexual and bisexual men; 123 were seropositive and 84 were seronegative. Principal Outcome Measures: Incident work disability in the course of 4.5 years of follow-up, with disability defined as a persistent (≥24 months) change in work hours (from 20 or more to less than 20 h/wk). Results: Compared with seronegative control subjects (n=72), the relative risk of work disability among initially asymptomatic seropositive men (n=44) was 2.76 (95% confidence interval, 1.2 to 6.5), nearly a threefold increase. Proportional hazards models show that this increased risk is attributable to the development of major neuropsychologic impairment in a subset (eight of 44) of the initially asymptomatic men, which is significantly associated with incident work disability (6/8 [75%]). Adjusting for symptom status and CD4+ cell count at the time of disability did not eliminate the increased risk associated with neuropsychologic impairment. Conclusions: In this cohort, the increased risk of work disability among initially asymptomatic human immunodeficiency virus—positive men was related to incident neuropsychologic impairment; such impairment predicted work disability independently of symptom status and CD4+ cell count over the follow-up period. Neuropsychologic impairment in the course of human immunodeficiency virus infection may indicate increased risk for poor outcomes over and above that associated with systemic disease
Recommended from our members
The Neuropsychological Profiles of Mild Alzheimer's Disease and Questionable Dementia as Compared to Age-Related Cognitive Decline
Test scores from a comprehensive neuropsychological battery administered to 1602 subjects consisting of 1347 subjects with probable Alzheimer's disease (AD), 100 subjects with questionable dementia (QD) and 155 non-demented elderly control subjects were cross-sectionally analyzed. Subjects with probable AD were categorized as mild (n = 244), moderate (n = 480), severe (n = 376), and very severe (n = 247) according to modified mini mental status exam (mMMSE) scores. Mean scores on individual neuropsychological tests are provided for each group of subjects. Stratified random sampling was performed to select a sample of mild AD subjects who were matched in age and education to non-demented elderly controls, and analyses focused on the performance of QD subjects and mild AD subjects, whose scores were compared to those of the elderly control subjects. Selected scores were organized by cognitive domain and logistic regressions were used to determine the domains and individual tests within each that were most predictive of group status. Results suggested a profile of scores associated with QD and mild AD including impaired recall of verbal information for both groups. Areas of lower functioning in QD subjects as compared to elderly controls included category fluency and visuospatial ability
Recommended from our members
Relationships between Extrapyramidal Signs and Cognitive Function in a Community-Dwelling Cohort of Patients with Parkinson's Disease and Normal Elderly Individuals
The relationship between extrapyramidal sign(DPS) severity and cognitive funcition was investigated in 184 patients with indiopathic Parkinson's disease (PD) and 301 normal elderly individuasls from a community-dwelling cohort in northern Manhattan, New York City. Fifiy-six of the patients with PD met criteria for dementia of the Diagnostic and Statistical Manual of Mental Disorders third edition, revised, and of the National Institute of Neurological and Communicative Disorders and Stroke-Alzbeimer's Disease and Related Disorders Association. EPS were rated according to the Unified Parkinson's Disease Rating Scale. Cognitive function was assessed by neuropsychological rests of memory, orientation, abstract reasoning, language, construcion, and psychomotor speed. Significant associations were found between EPS and neuropsychological performance in PD partients without dementia. Yet EPS severity was unable to account for the pronounced cognitive impairment in PD dementia. Individuals in the normal group with subtle EPS, but withtout overt idiopathic PD, showed widespread cognitive changes, including imparment in most of the tests that differentiated PD patients from normal subjects. Prospective follow-up of these individuals will determine whether this represents a preclinical stage of PD or constitutes an early manifestation of dementia
- …