Biomedical subjects

D B Allison

Publications and source records attributed to D B Allison.

At least 73 records · Page 4Linked to original sources

PubMed2001

Evaluating subject-treatment interaction when comparing two treatments.

Clinical and other studies that evaluate the effect of a treatment relative to a control often focus on estimating a mean treatment effect; however, the mean treatment effect may be misleading when the effect of the treatment varies widely across subjects. Methods are proposed to evaluate individual treatment heterogeneity (i.e., subject-treatment interaction) and its consequences in clinical experiments. The method of maximum likelihood is used to derive estimators and their properties. A bootstrap procedure that requires fewer assumptions is also presented as a small sample alternative to the maximum likelihood approach. It is shown that estimators for subject-treatment interaction are sensitive to an inestimable correlation parameter. This sensitivity is illustrated using some example data sets and using graphical plots. The practical consequence of subject-treatment interaction is that a proportion of the population may be not be responding to the treatment as indicated by the average treatment effect. Results obtained from the methods reported here can alert the practitioner to the possibility that individual treatment effects vary widely in the population and help to assess the potential consequences of this variation. Applications of the proposed procedures to clinical decision making, pharmacogenetic studies, and other contexts are discussed.

Algorithms↗

PubMed2000

Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia.

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection, the data have been controversial. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development.

AIDS Vaccines↗

PubMed2000

Testing the robustness of the new Haseman-Elston quantitative-trait loci-mapping procedure.

Variance components (VC) techniques have emerged as among the more powerful methods for detection of quantitative-trait loci (QTL) in linkage analysis. Allison et al. found that, with particularly marked leptokurtosis in the phenotypic distribution and moderate-to-high residual sibling correlation, maximum likelihood (ML) VC methods may produce a severe excess of type I errors. The new Haseman-Elston (NHE) method is a least-squares-based VC method for mapping of QTL in sib pairs (Elston et al.). Using simulation, we investigate the robustness of the NHE to marked nonnormality, by means of the same distributions and worst-case conditions identified by Allison et al. for the ML approach (i.e., 100 pairs; high residual sibling correlation). Results showed that, when marked nonnormality is present, the NHE can be used without severe type I error-rate inflation, even at very small alpha levels.

Chromosome Mapping↗

PubMed2000

Obesity in North America. An overview.

The terms "obesity" and "overweight" mean different things to different people. This article discusses such issues as prevalence, morbidity, mortality, and psychosocial effects. Definitions and various classifications of obesity are discussed also.

Adolescent↗

PubMed2000

Intrapair resemblance in very low calorie diet-induced weight loss in female obese identical twins.

OBJECTIVE: To assess intrapair resemblance in changes of body weight, total body fat, fat distribution, resting metabolic rate, fasting respiratory quotient and cardiovascular disease risk factors in response to therapeutic weight loss in female obese identical twins. DESIGN: Patients stayed for 40 days on an inpatient metabolic unit under careful supervision. The stay was divided into three parts: an initial period of 7 days for adjustment to the hospital environment and for baseline measurements, 28 days of the weight reduction regimen when negative energy balance was achieved mainly by a very low calorie diet (1.6 MJ per day) and 5 days of testing after weight reduction. SUBJECTS: Fourteen pairs of premenopausal female obese identical twins (age: 39.0+/-1.7 y; body weight (BW): 93.9+/-21.2 kg; body mass index (BMI): 34.2+/-7.8 kg/m2) participated in the study. MEASUREMENTS: Before and after weight loss, the following measurements were made: body composition by anthropometry and hydrodensitometry, intra-abdominal fat by ultrasonography, resting metabolic rate by indirect calorimetry. Total cholesterol, high-density lipoprotein-cholesterol, triglycerides and uric acid were determined by standard laboratory procedures. Blood pressure was measured in the morning in the recumbent position. RESULTS: Subjects lost 8.8+/-1.9 kg of weight, from 93.9+/-21.2 to 85.1+/-10.9 kg (P<0.0001) and 6.5+/-2.3 kg of body fat (P<0.001). Weight losses varied widely among subjects, with a high correlation between losses of members of twin pairs for body weight (r=0.85; P<0.001) and for body fat (r=0.88; P<0.0001). Changes in uric acid resulting from weight loss were also correlated among members of twin pairs whereas changes in blood pressure, cholesterol and triglycerides were not. CONCLUSION: The great intrapair resemblance observed in very low calorie diet-induced weight and fat losses in female obese identical twins suggests an important role of genetic factors in response to the weight reduction regimen.

Adipose Tissue↗

PubMed2000

Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle.

In laboratory rodents, caloric restriction (CR) retards several age-dependent physiological and biochemical changes in skeletal muscle, including increased steady-state levels of oxidative damage to lipids, DNA, and proteins. We used immunogold electron microscopic (EM) techniques with antibodies raised against 4-hydroxy-2-nonenal (HNE) -modified proteins, dinitrophenol, and nitrotyrosine to quantify and localize the age-dependent accrual of oxidative damage in rhesus monkey vastus lateralis skeletal muscle. Using immunogold EM analysis of muscle from rhesus monkeys ranging in age from 2 to 34 years old, a fourfold maximal increase in levels of HNE-modified proteins was observed. Likewise, carbonyl levels increased approximately twofold with aging. Comparing 17- to 23-year-old normally fed to age-matched monkeys subjected to CR for 10 years, levels of HNE-modified proteins, carbonyls, and nitrotyrosine in skeletal muscle from the CR group were significantly less than control group values. Oxidative damage largely localized to myofibrils, with lesser labeling in other subcellular compartments. Accumulation of lipid peroxidation-derived aldehydes, such as malondialdehyde and 4-hydroxy-2-alkenals, and protein carbonyls were measured biochemically and confirmed the morphological data. Our study is the first to quantify morphologically and localize the age-dependent accrual of oxidative damage in mammalian skeletal muscle and to demonstrate that oxidative damage in primates is lowered by CR.

Animals↗

PubMed2000

Behavioral approaches to the problems of obesity.

Obesity is a complex and increasingly prevalent disorder that can confer a number of medical, social, and psychological difficulties. As a result, an array of treatment strategies falling under the generic umbrella of "behavior therapy" have been developed and continue to be refined and expanded. In this article, different behavioral approaches to the problems of obesity are outlined and reviewed, specifically, those that target (a) body weight or composition, (b) lifestyle factors and other health-related variables, and (c) related psychological variables such as self-esteem and assertiveness, as well as negative attitudes toward obese persons held by nonobese individuals. For each of these targets of change, approaches to both individual- and group-level interventions are considered. Suggestions for future research and clinical work are offered. Throughout, the importance of conceptualizing obesity as a multifaceted problem is underscored. The necessity for explicit target goals when attempting to modify behavior is also highlighted.

Behavior Therapy↗

PubMed2000

Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study.

OBJECTIVES: This study sought to test the relationships between relative body weight and clinical depression, suicide ideation, and suicide attempts in an adult US general population sample. METHODS: Respondents were 40,086 African American and White participants interviewed in a national survey. Outcome measures were past-year major depression, suicide ideation, and suicide attempts diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The primary predictor was relative body weight, treated both continuously (i.e., body mass index [BMI]) and categorically in logistic regression analyses. Covariates included age, income and education, disease status, and drug and alcohol use. RESULTS: Relative body weight was associated with major depression, suicide attempts, and suicide ideation, although relationships were different for men and women. Among women, increased BMI was associated with both major depression and suicide ideation. Among men, lower BMI was associated with major depression, suicide attempts, and suicide ideation. There were no racial differences. CONCLUSIONS: Differences in BMI, or weight status, were associated with the probability of past-year major depression, suicide attempts, and suicide ideation. Longitudinal studies are needed to differentiate the causal pathways and mechanisms linking physical and psychiatric conditions.

Adult↗

PubMed1999

Annual deaths attributable to obesity in the United States.

CONTEXT: Obesity is a major health problem in the United States, but the number of obesity-attributable deaths has not been rigorously estimated. OBJECTIVE: To estimate the number of deaths, annually, attributable to obesity among US adults. DESIGN: Data from 5 prospective cohort studies (the Alameda Community Health Study, the Framingham Heart Study, the Tecumseh Community Health Study, the American Cancer Society Cancer Prevention Study I, and the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study) and 1 published study (the Nurses' Health Study) in conjunction with 1991 national statistics on body mass index distributions, population size, and overall deaths. SUBJECTS: Adults, 18 years or older in 1991, classified by body mass index (kg/m2) as overweight (25-30), obese (30-35), and severely obese (>35). MAIN OUTCOME MEASURE: Relative hazard ratio (HR) of death for obese or overweight persons. RESULTS: The estimated number of annual deaths attributable to obesity varied with the cohort used to calculate the HRs, but findings were consistent overall. More than 80% of the estimated obesity-attributable deaths occurred among individuals with a body mass index of more than 30 kg/m2. When HRs were estimated for all eligible subjects from all 6 studies, the mean estimate of deaths attributable to obesity in the United States was 280184 (range, 236111-341153). Hazard ratios also were calculated from data for nonsmokers or never-smokers only. When these HRs were applied to the entire population (assuming the HR applied to all individuals), the mean estimate for obesity-attributable death was 324 940 (range, 262541-383410). CONCLUSIONS: The estimated number of annual deaths attributable to obesity among US adults is approximately 280000 based on HRs from all subjects and 325000 based on HRs from only nonsmokers and never-smokers.

Adult↗

PubMed1999

Meta-analysis of the effect of excluding early deaths on the estimated relationship between body mass index and mortality.

OBJECTIVES: Prospective cohort studies typically observe U- or J-shaped relationships between body mass index (BMI) (kg/m2) and mortality. However, some studies suggest that the elevated mortality at lower BMIs is due to confounding by pre-existing occult disease and recommend eliminating subjects who die during the first several (k) years of follow-up. This meta-analysis tests the effects of such early death exclusion on the BMI-mortality association. RESEARCH METHODS AND PROCEDURES: Studies identified from MEDLINE, review articles, ancestry analyses, and the "invisible college." INCLUDED STUDIES: 1) measured relative body weight at baseline; 2) included at least 1000 subjects; 3) reported results with and without early-death exclusion, or relevant data; and 4) did not study exclusively diseased populations. Blank tables were mailed to 131 investigators covering 59 databases. Completed tables (n = 16 databases), electronic raw data (n = 7 databases), and original articles (n = 6 databases) provided final data. Meta-analytic regressions compared the BMI-mortality association with and without early death exclusion. The sample included 29 studies and 1,954,345 subjects. RESULTS: The effect of eliminating early deaths was statistically significant but minuscule in magnitude. Implementation of early death exclusion was estimated to shift the BMI associated with minimum mortality only 0.4 units for men and 0.6 units for women at age 50. Even at a BMI 16, the estimated relative risk (compared to BMI 25) decreased only 0.008 units for men and 0.076 units for women at age 50. DISCUSSION: Results indicate that either pre-existing disease does not confound the BMI-mortality association or eliminating early deaths is inefficient for reducing that confounding.

Adolescent↗

PubMed1999

Is the prevalence of successful weight loss and maintenance higher in the general community than the research clinic?

OBJECTIVE: The prevalence of successful weight loss remains unclear. In 1982, Schachter concluded that in the general population, the rate of "self-cured" obesity approached 63%-much higher than the rate from clinical trials. Several subsequent studies have addressed this issue. RESEARCH METHODS AND PROCEDURES: Our initial goal was to meta-analyze these studies to evaluate the validity of the original hypotheses and the extent to which additional investigations supported the findings. We began by restating Schachter's hypotheses in precise, testable terms. RESULTS: A systematic review of these studies found many methodological limitations and much heterogeneity among the samples studied, hypotheses addressed, and operational definitions. Some of these limitations appear to stem from the lack of clear, precise statements of the exact hypotheses tested. Differences among studies are delineated, and we outline why meta-analytic pooling of these data appears inappropriate. CONCLUSIONS: The current data are inadequate to draw any definite conclusions regarding the cure rate of obesity. Criteria for the adequate study of success rates with "self-cure" in the general population are proposed.

Female↗

PubMed1999

Estimated intakes of trans fatty and other fatty acids in the US population.

OBJECTIVE: To estimate mean level of trans fatty acid intakes using a representative sample of the US population. DESIGN: The study used food intake data from the 1989-1991 Continuing Survey of Food Intakes by Individuals (CSFII) and the trans fatty acid contents of specific foods calculated from a database compiled by the US Department of Agriculture (USDA) to estimate the mean level and deciles of trans fatty acid intake of the representative US population. SUBJECTS/SETTING: Trans fatty acid intakes were estimated for each subject (N = 11,258) in the CSFII data who completed both a 24-hour recall and a 2-day food record. STATISTICAL ANALYSES PERFORMED: Weights developed by USDA for the survey were used for all data analyses. The Technical Assessment Systems (TAS) International Diet Research System (TAS-DIET), software developed by TAS, was used to derive weighted estimates of the mean and percentiles of the intake distribution. PC CARP, software designed by Iowa State University, was used to estimate standard errors. RESULTS: Mean percentage of energy ingested as trans fatty acids was 2.6% and the mean percentage of total fat ingested as trans fatty acids was 7.4%. Across all age and gender groups examined, estimates ranged from 2.6% to 2.8% and 7.1% to 7.9%, respectively. APPLICATIONS/CONCLUSIONS: Dietetics practitioners can use the representative data of this study to help clients achieve desired changes in consumption levels of trans fatty acids.

Adolescent↗

PubMed1999

Simulation study of the effects of excluding early deaths on risk factor-mortality analyses in the presence of confounding due to occult disease: the example of body mass index.

PURPOSE: Estimating the effects of continuous chronic disease risk factors on mortality is an area that generates confusion and controversy. The frequently observed U-shaped or J-shaped relationships between the risk factors and mortality are often in contrast with presumed monotone relationships. Therefore, some investigators suggest that subjects dying during the first k years of follow-up (where k is some positive number less than the total length of follow-up) be excluded from statistical analyses. The rationale for this approach is that subjects dying during the first k years of follow-up are likely to have some pre-existing occult disease that confounds the relationship between the risk factors and mortality. Excluding such subjects purportedly reduces bias due to this confounding. The purpose of this study was to test the effects of excluding subjects who die during the first k years of follow-up on the reduction of bias under a variety of situations. METHODS: Using body mass index (BMI; kg/m2) as an example, we conducted Monte Carlo simulations to investigate such effects. RESULTS: Results suggest that under the conditions investigated, the method of excluding early deaths does not reliably or substantially reduce bias due to confounding introduced by occult disease. CONCLUSION: Excluding subjects dying during the first k years of follow-up may not be a judicious strategy for handling confounding due to occult disease. Investigators are encouraged to develop alternative methods.

Bias↗

PubMed1999

Evidence for genetic influences on human energy intake: results from a twin study using measured observations.

Human obesity is associated with greater-than-average energy intake, although relatively few studies have tested the heritability of food intake. The present study examined the genetic architecture of measured caloric intake during laboratory test meals in 36 monozygotic and 18 dizygotic twin pairs. A series of analyses tested the hypotheses that (1) there would be a genetic influence on total caloric intake, (2) there would be genes influencing total caloric intake above and beyond those influencing body composition, (3) there would be a phenotypic association between total caloric intake and fat mass above and beyond any genetic influences, and (4) there would be genetic influences on macronutrient intake (i.e., fat, carbohydrate, and protein intake) above and beyond total caloric intake. Results suggested genetic influences on age- and sex-adjusted total caloric intake (24-33% of the variance), although 95% confidence intervals were wide and suggested that "true" heritability estimates might be considerably lower or higher. Caloric intake was influenced by both common and unique environmental factors. Greater-than-average caloric intake was associated with increased adiposity, despite probable genetic influences on both phenotypes. Finally, there was evidence for macronutrient-specific familial influences, although the extent to which they were genetic or environmental in origin could not be teased apart. Results suggest that human obesity may be influenced by behaviors that are themselves genetically regulated. However, further studies are needed to obtain more precise heritability estimates and a better understanding of the conditions under which genetic influences on energy intake emerge.

Adult↗

PubMed1999

Weight loss increases and fat loss decreases all-cause mortality rate: results from two independent cohort studies.

OBJECTIVE: In epidemiological studies, weight loss is usually associated with increased mortality rate. Contrarily, among obese people, weight loss reduces other risk factors for disease and death. We hypothesised that this paradox could exist because weight is used as an implicit adiposity index. No study has considered the independent effects of weight loss and fat loss on mortality rate. We studied mortality rate as a function of weight loss and fat loss. DESIGN: Analysis of 'time to death' in two prospective population-based cohort studies, the Tecumseh Community Health Study (1890 subjects; 321 deaths within 16y of follow-up) and the Framingham Heart Study (2731 subjects; 507 deaths within 8y of follow-up), in which weight and fat (via skinfolds) loss were assessable. RESULTS: In both studies, regardless of the statistical approach, weight loss was associated with an increased, and fat loss with a decreased, mortality rate (P < 0.05). Each standard deviation (s.d.) of weight loss (4.6 kg in Tecumseh, 6.7 kg in Framingham) was estimated to increase the hazard rate by 29% (95% confidence interval CI), (14%, 47%, respectively) and 39% (95% CI, 25%, 54% respectively), in the two samples. Contrarily, each s.d. of fat loss (10.0 mm in Tecumseh, 4.8 mm in Framingham) was estimated to reduce the hazard rate 15% (95% CI, 4%, 25%) and 17% (95% CI, 8%, 25%) in Tecumseh and Framingham, respectively. Generalisability of these results to severely (that is, body mass index BMI) > or = 34) obese individuals is unclear. CONCLUSIONS: Among individuals that are not severely obese, weight loss is associated with increased mortality rate and fat loss with decreased mortality rate.

Adipose Tissue↗

PubMed1999

The long isoform uncoupling protein-3 (UCP3L) in human energy homeostasis.

The biological role(s) proposed for UCP3 in energy homeostasis have been based primarily upon amino acid sequence homology to UCP1. Spontaneous mutations of UCP3> have been described in humans, but not in rodents. The functional consequences-or lack thereof-of these mutations in humans will be of great importance in elucidating the biology of this protein. The results of two such studies are summarized here.

Animals↗

PubMed1999

Sibling-based tests of linkage and association for quantitative traits.

The transmission/disequilibrium test (TDT) developed by Spielman et al. can be a powerful family-based test of linkage and, in some cases, a test of association as well as linkage. It has recently been extended in several ways; these include allowance for implementation with quantitative traits, allowance for multiple alleles, and, in the case of dichotomous traits, allowance for testing in the absence of parental data. In this article, these three extensions are combined, and two procedures are developed that offer valid joint tests of linkage and (in the case of certain sibling configurations) association with quantitative traits, with use of data from siblings only, and that can accommodate biallelic or multiallelic loci. The first procedure uses a mixed-effects (i.e., random and fixed effects) analysis of variance in which sibship is the random factor, marker genotype is the fixed factor, and the continuous phenotype is the dependent variable. Covariates can easily be accommodated, and the procedure can be implemented in commonly available statistical software. The second procedure is a permutation-based procedure. Selected power studies are conducted to illustrate the relative power of each test under a variety of circumstances.

Genetic Linkage↗

PubMed1999

Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure.

Detection of linkage to genes for quantitative traits remains a challenging task. Recently, variance components (VC) techniques have emerged as among the more powerful of available methods. As often implemented, such techniques require assumptions about the phenotypic distribution. Usually, multivariate normality is assumed. However, several factors may lead to markedly nonnormal phenotypic data, including (a) the presence of a major gene (not necessarily linked to the markers under study), (b) some types of gene x environment interaction, (c) use of a dichotomous phenotype (i.e., affected vs. unaffected), (d) nonnormality of the population within-genotype (residual) distribution, and (e) selective (extreme) sampling. Using simulation, we have investigated, for sib-pair studies, the robustness of the likelihood-ratio test for a VC quantitative-trait locus-detection procedure to violations of normality that are due to these factors. Results showed (a) that some types of nonnormality, such as leptokurtosis, produced type I error rates in excess of the nominal, or alpha, levels whereas others did not; and (b) that the degree of type I error-rate inflation appears to be directly related to the residual sibling correlation. Potential solutions to this problem are discussed. Investigators contemplating use of this VC procedure are encouraged to provide evidence that their trait data are normally distributed, to employ a procedure that allows for nonnormal data, or to consider implementation of permutation tests.

Analysis of Variance↗