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Biomedical subjects

R Brookmeyer

Publications and source records attributed to R Brookmeyer.

At least 19 recordsLinked to original sources
PubMed1997

Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.

Anti-HIV Agents↗
PubMed1997

Regression analysis of discrete time survival data under heterogeneity.

This paper concerns the regression analysis of discrete time survival data for heterogeneous populations by means of frailty models. We express the survival time for each individual as a sequence of binary variables that indicate if the individual survived at each time point. The main result is that the likelihood for these indicators can be factored into contributions that involve the conditional survival probabilities integrated over the frailty distribution of the risk set (population-averaged). We then model these population-averaged conditional probabilities as a function of covariates. The result justifies the practice of treating the failure indicators as independent Bernoulli trials and fitting binary regression models for the conditional failure probabilities at each time point. However, we must interpret the regression coefficients as population-averaged rather than subject-specific parameters. We apply the method to the Framingham Heart Study on risk factors for cardiovascular disease.

Algorithms↗
PubMed1997

Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.

Anti-HIV Agents↗
PubMed1997

Predictors of stroke risk in coronary artery bypass patients.

BACKGROUND: Stroke occurs after coronary artery bypass grafting with an incidence ranging between 0.8% and 5.2%. To identify factors associated with stroke, we prospectively examined a study cohort and tested findings in an independent validation sample. METHODS: The study cohort comprised 456 patients undergoing coronary artery bypass grafting only, and the validation sample comprised 1,298 patients. Stroke was detected postoperatively by the study team and confirmed by neurologic consultation and computed tomographic scanning. RESULTS: Five factors taken together were correlated with stroke: previous stroke, presence of carotid bruit, history of hypertension, increasing age, and history of diabetes mellitus. The only significant intraoperative factor was cardiopulmonary bypass time. Probabilities were calculated, and patients were placed into low, medium, and high stroke-risk groups. In the validation sample, this model was able to rank the majority of patients with stroke into the high-risk group. CONCLUSIONS: These five factors taken together can identify the risk of stroke in patients having coronary artery bypass grafting. Recognition of the high-risk group will aid studies on the mechanism and prevention of stroke by modification of surgical procedures or pharmacologic intervention.

Aged↗
PubMed1997

Definitions of genital ulcer disease and variation in risk for prevalent human immunodeficiency virus infection.

OBJECTIVES: Although genital ulcer disease (GUD) has been associated with human immunodeficiency virus (HIV) infection in a number of studies, definitions of genital ulceration have varied. The authors hypothesized that the association of GUD with prevalent HIV infection may vary according to the definition of GUD that is used. METHODS: As part of a prospective cohort study, 863 patients were interviewed and examined who presented to a sexually transmitted disease (STD) clinic for new symptom evaluation and who agreed to HIV testing to determine demographic and behavioral risk associated with prevalent HIV infection. To determine the association between GUD and prevalent HIV, the following definitions of GUD were used: observed ulcers, history of syphilis, serologic evidence of syphilis, observed culture-proven genital herpes, and serologic evidence of herpes simplex virus type II (HSV-2) infection. RESULTS: Of 481 men and 382 women enrolled, prevalent HIV infection was detected in 12.5% and 5.2%, respectively. In multivariate analyses controlling for known HIV risk behaviors, prevalent HIV infection was associated with observed GUD (odds ratio [OR] = 2.0, 95% confidence intervals (CI) = 1.0-3.9), a history of syphilis (OR = 6.0, CI = 2.8-12.7), and serologic evidence of syphilis (OR = 3.7, CI = 1.9-7.0), but not with serologic evidence of HSV-2 (OR = 1.2, CI = 0.7-2.1), nor with observed HSV-2 culture-positive genital ulcerations (OR = 1.0, CI = 0.4-4.2). Factors contributing to different strengths of association between HIV infection and a history of syphilis or serologic evidence of syphilis included the presence of underdiagnosed syphilis infection in people with reactive serologic tests and the absence of serologic reactivity in people with a positive history. CONCLUSIONS: Although GUD is strongly associated with prevalent HIV, the strength of the association depends on the definition of GUD used. For accurate evaluation of people at risk for HIV, clinicians and researchers should use multiple definitions of GUD.

Adolescent↗
PubMed1997

A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging.

Previous reports have suggested that estrogen replacement therapy (ERT) in women may exert a protective effect on their risk of developing Alzheimer's disease (AD). We investigated this relationship in the Baltimore Longitudinal Study of Aging (BLSA), a prospective multidisciplinary study of normal aging conducted by the National Institute on Aging. The sample consisted of 472 post- or perimenopausal women followed for up to 16 years in the BLSA. We documented ERT prospectively at each BLSA visit, and we categorized women who had used oral or transdermal estrogens at anytime as ERT users. We used Cox proportional hazards models with time-dependent covariates to estimate the relative risk of developing AD after ERT as compared with women who had not used estrogen replacement. Approximately 45% of the women in the cohort had used ERT, and we diagnosed 34 incident cases of AD (NINCDS/ADRDA criteria) during follow-up, including nine estrogen users. After adjusting for education, the relative risk for AD in ERT users as compared with nonusers was 0.46 (95% CI, 0.209-0.997), indicating a reduced risk of AD for women who had reported the use of estrogen. Our data did not show an effect for duration of ERT usage. Our finding offers additional support for a protective influence of estrogen in AD. Randomized clinical trials are necessary to confirm this association, which could have significant public health impact.

Adult↗
PubMed1996

Suicide and HIV infection. Mortality follow-up of 4147 HIV-seropositive military service applicants.

OBJECTIVE: To examine the risk of suicide among individuals positive for the human immunodeficiency virus (HIV) following screening for evidence of HIV infection. Prior studies have reported a 7- to 36-fold increased risk of suicide for persons with the acquired immunodeficiency syndrome. DESIGN: Prospective cohort study. SETTING: Military service applicants from throughout the United States. MAIN OUTCOME MEASURE: Death from suicide. METHODS: The National Death Index was searched for mortality among 4147 HIV-positive military service applicants and 12437 HIV-negative applicants disqualified from military service due to other medical conditions (matched 1:3 on age, race, sex, and screening date and location) identified by the US Department of Defense between October 1985 and December 1993. Death certificates were obtained from individual states. Identifiers and HIV status of living applicants were known only by the Department of Defense. RESULTS: The HIV-positive applicants were 92% male, 37% white, and 56% black. Median age was 24 years (range, 17-57 years). Median follow-up time was 70 months (range, 0-99 months). Ten HIV-positive (49 per 100 000 person-years) and 24 HIV-negative applicants (36 per 100 000 person-years) died of suicide (rate ratio [RR], 1.35; 95% confidence interval [CI]= 0.58-2.93). Suicide rates among both HIV-positive (RR, 2.08; 95% CI, 1.00-3.82) and HIV-negative (RR, 1.67; 95% CI, 1.07-2.48) applicants are marginally higher than those for the US general population, after adjustment for age, race, and sex. Time from screening to death was less than 3 months for 3 of 10 HIV-positive and 2 of 24 HIV-negative applicants who died of suicide. CONCLUSIONS: The HIV-positive individuals do not appear to have a significantly increased risk of death from suicide in the months following HIV screening in this study population. Because suicide risk is reported to be greatly increased after symptomatic HIV disease is present, clinicians should consider asking persons with HIV infection about suicide risk factors during both initial counseling and subsequent medical care.

AIDS Serodiagnosis↗
PubMed1996

Measuring HIV-1 incidence in northern Thailand: prospective cohort results and estimates based on early diagnostic tests.

Measuring the incidence of the human immunodeficiency virus (HIV) is of vital importance but can be difficult and costly. We compared HIV-1 incidence measured directly from prospective cohort studies with rates derived from a method using the prevalence of HIV-1 antibody-negative, p24-antigen-positive individuals. Male and female commercial sex workers (CSWs) were enrolled and followed in separate cohort studies in northern Thailand between 1989 and 1994, and HIV incidence was measured by prospective follow-up of individuals seronegative at baseline. In 1991-1992 cross-sectional serosurveys were done among male and female CSWs in the same region; all HIV-1 antibody-negative subjects in these surveys were tested for p24 antigenemia. HIV incidence was estimated using the prevalence of p24 antigen and a model based on the mean duration of p24 antigenemia before HIV antibody detection. The cohort studies showed high initial incidence rates-23.8/100 person-years (PY) among female CSWs and 11.9/100 PY among male CSWs-but poor compliance with prospective follow-up. Subjects lost to follow-up appeared to be at greater risk of HIV seroconversion than those retained. The p24 antigen method estimate among female CSWs, 25.4%/year, was quite similar to the initial incidence rate found in the cohort. The estimate by the p24 antigen method was higher, 19.9%/year, among male CSWs than that measured prospectively. In populations with high rates of HIV transmission and in whom long-term follow-up is incomplete, estimates of incidence using p24 antigen prevalence among antibody-negative subjects can give useful and economical estimates of HIV incidence and allow for estimates of whether the incidence rates are similar in subjects successfully followed and those lost to follow-up.

Adolescent↗
PubMed1996

Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease.

BACKGROUND: The risk of Alzheimer's disease (AD) appears to increase, and the age at onset to decrease, with the number of epsilon 4 alleles. If this relationship is due to increased rate of pathophysiological change, the presence of epsilon 4 would be expected to influence progression of disease, predicting a more rapid decline with increasing number of epsilon 4 alleles. OBJECTIVE: To determine if the frequency of the epsilon 4 allele of the apolipoprotein E (ApoE) gene affects the rate of clinical progression in AD. SETTING: Alzheimer's Disease Research Center. SUBJECTS: One hundred one subjects meeting criteria of the National Institute of Neurological Disorders and Stroke for probable AD or of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) for definite AD; 78 of these subjects met the additional criterion of having a Mini-Mental State Examination score of at least 10 for analysis of rate of decline. MEASUREMENTS: The subjects' characteristics and neuropsychological battery, including the Mini-Mental state Examination, Spatial Delayed Recognition Span, Boston Naming Test, Category Fluency Test, and the Physical Capacity Subscale of the Psychogeriatric Dependency Rating Scale. DESIGN: The subjects were followed up longitudinally for approximately one decade. Medical histories were taken and physical and neurologic examinations and neuropsychological testing were performed every 6 months. Three and a half years of data were available for most tests and 5.5 for the Psychogeriatric Dependency Rating Scale; thereafter, patients were no longer testable. A general linear model analysis of variance was used to assess the influence of ApoE on demographic characteristics and baseline performances on neuropsychological measures. A random-effects regression model was used to predict change over time associated with presence of epsilon 4 on clinical and cognitive measures. RESULTS: The age at onset was greatest for the epsilon 4-heterozygous subjects and least for the epsilon 4-negative subjects. The heterozygous subjects declined more rapidly on the Mini-Mental State Examination and the Category Fluency Test than the subjects without the epsilon 4 allele or with epsilon homozygosity. The homozygous subjects declined faster on only one subscale: the Physical Capacity subscale of the Psychogeriatric Dependency Rating Scale. Covarying for age at onset did not affect the results. CONCLUSIONS: The ApoE genotype does not strongly influence the rate of decline in AD, implying that epsilon 4 might predispose to the development of the disease without accelerating its pathogenesis or progression. The effects of epsilon 4 on both age at onset and rate of decline need to be further investigated.

Age of Onset↗
PubMed1996

Predicting rate of cognitive decline in probable Alzheimer's disease.

Recent attempts to identify predictors of rate of decline in Alzheimer's disease (AD) have been extremely variable in choice of outcome variables, predictor variables tested, timing of assessments, and statistical approaches. In this study, a random effects regression model was applied to seek predictors of decline on the Mini-Mental State Exam in 132 patients with probable AD reassessed every 6 months for up to 7.5 years. Potential predictor variables at baseline were of three types: patients characteristics, clinical variables, and cognitive performances. The final multivariate analysis indicated that the following characteristics predicted more rapid cognitive decline: more education, history of dementia in a first degree relative, non-right handedness, better performances of Boston Naming Test, Gollin Incomplete Figures Test, and Benton Visual Retention Test-Delay, and worse performances on Responsive Naming Test, WAIS-R Block Design, and Benton Visual Retention Test-Copy.

Age of Onset↗
PubMed1996

Differences in the incidence of hepatitis B and human immunodeficiency virus infections among injecting drug users.

Both hepatitis B virus (HBV) and human immunodeficiency virus (HIV) type 1 seroconversions have been considered as outcome measures to evaluate the effectiveness of needle exchange programs. To assess the relationships between incident HBV and HIV infections among injecting drug users (IDUs), seroconversions were prospectively studied among a cohort of 240 HBV- and HIV- seronegative IDUs. The incidence of HBV seroconversion declined from 24.41/100 person-years in 1988 to 0 seroconversions in 1992. In contrast, HIV seroconversion rates varied little from the overall rate of 3.29/100 person-years. HBV seroconversion predicted subsequent HIV seroconversion among male IDUs (relative incidence [RI]= 4.23) but not among female IDUs (RI=0.86). Because of different transmission dynamics, HBV seroconversion probably has limited utility as a surrogate outcome measure for incident HIV. However, HBV seroconversion itself is an appropriate and important outcome measure for evaluation of prevention programs among IDUs.

Adult↗
PubMed1996

Statistical issues in prevention and therapeutic trials of Alzheimer disease.

Relatively little attention has been given to the proper design and statistical analysis of prevention and therapeutic trials of Alzheimer disease (AD). A number of important methodological issues arise in studies of AD that do not typically arise in studies of other chronic diseases. These issues include: the definition of the primary study endpoint that is simple to measure and easy to interpret; proper design of trials that take into account that the patient population is very old; and the proper statistical analysis that addresses the high drop out rate and the multiple ways of measuring disease severity. Addressing these issues will speed the progress of the evaluation of promising compounds to prevent and treat AD.

Alzheimer Disease↗
PubMed1996

AIDS, epidemics, and statistics.

Statistical thinking has made significant contributions to our understanding of epidemics. Examples where statistics has played an important role in the Acquired Immunodeficiency Syndrome (AIDS) epidemic include estimating the number of individuals infected with the human immunodeficiency virus, estimating the incubation period of the disease, studying the etiology of the disease, and monitoring and forecasting the course of the epidemic. Some parallels with other epidemics in history are drawn. The AIDS epidemic has also raised important questions about the design of clinical studies and whether classical approaches are sufficiently flexible to provide timely answers to therapeutic questions in a growing epidemic. In a public crisis, there is a sense of urgency and data may be collected with unusual sampling schemes and inherent biases. Attention needs to be paid as much to sampling variation as to systematic sources of bias. Accurate disease surveillance data and methods for analyzing such data are crucial for detecting and monitoring future epidemics. There will almost certainly be new epidemics in the future, either of old diseases resurfacing or of new diseases, and statistical reasoning will continue to play a significant role in addressing the challenges of these public health crises.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The AIDS epidemic in India: a new method for estimating current human immunodeficiency virus (HIV) incidence rates.

Human immunodeficiency virus (HIV) incidence rates in India were estimated using a new method that accounts for follow-up bias. Follow-up bias arises in epidemiologic cohort studies when the incidence rate among individuals who do and do not return for follow-up are different. The new method combines data on the prevalence of p24 antigenemia among all those initially screened together with the longitudinal follow-up data on the subset of patients who returned for follow-up. Using these methods, the current HIV incidence rate among patients attending sexually transmitted disease clinics in Pune, India, was 18.6% per year. It was found that follow-up bias can cause significant underestimation in HIV incidence rates, perhaps by as much as 60%. These incidence estimates, together with other HIV seroprevalence studies, suggest the HIV epidemic in India is growing rapidly.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Estimation of current human immunodeficiency virus incidence rates from a cross-sectional survey using early diagnostic tests.

In sharp contrast to the considerable worldwide epidemiologic data available on acquired immunodeficiency syndrome incidence and human immunodeficiency virus (HIV) seroprevalence, there is relatively little information about current levels of HIV incidence rates. The authors suggest a novel approach for estimating current HIV incidence rates based on a single cross-sectional survey and on an epidemiologic model. The approach is based on diagnostic tests for HIV p24 antigen to identify individuals in the preantibody or window period (time between exposure to HIV and appearance of detectable HIV antibodies). Individuals in the preantibody period are likely to have been infected very recently because the duration of the preantibody period is relatively short. The authors report data on the duration of p24 antigenemia prior to HIV seroconversion. This duration together with the prevalence of p24 antigenemia obtained from a cross-sectional survey are used in an epidemiologic model to estimate current incidence rates. This approach of estimating incidence rates may be especially useful in developing countries and high-risk populations in which it is difficult to follow cohorts to identify seroconverters, and in the design of vaccine efficacy studies in which current incidence rates are crucial for calculating sample sizes.

Cross-Sectional Studies↗
PubMed1995

Managed mental health care and patterns of inpatient utilization for treatment of affective disorders.

In this analysis we made use of a large data base of individuals insured by large American corporations to estimate the impact of managed care provision on hospital care for depression. Data on 6,348 individuals hospitalized for depression were examined to assess the effect of managed care techniques on the cost per episode and the likelihood of rehospitalization. Preadmission certification programs were found to lead to significant long- and short-run savings for payers.

Adult↗
PubMed1995

Sources of variability in prevalence rates of Alzheimer's disease.

OBJECTIVE: To investigate potential methodological reasons for the differences in published Alzheimer's disease (AD) prevalence rates. BACKGROUND: Studies reporting prevalence rates of AD have been published worldwide. These rates differ considerably, but may greatly reflect methodological differences. METHODS: All studies published between 1984 and 1993 that reported age-specific AD rates and sample sizes were included. Logistic regression identified variables that contribute to the variation in rates. Estimates of extrabinomial variation were also calculated. RESULTS: Studies characterized by the following features yielded significantly higher rates: inclusion of mild cases, use of laboratory studies, ascertainment of a sample rather than the total population, inclusion of both urban and rural populations, non-use of computerized tomography (CT) scans, non-use of the Hachinski Ischemic Score, and no adjustment for false negatives. The odds of having AD increased 18% for every year of age. The variation in the age-specific prevalence rates of AD was approximately 15 times that expected by sampling variation. However, approximately 76% of this excess variation in rates could be accounted for by methodological differences. CONCLUSIONS: After accounting for age, much of the variability in prevalence rates of AD in the published literature may be explained by differences in methodology. Some unexplained variation in prevalence rates, however, still remains.

Age Factors↗