Glen A. Satten

Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection

BACKGROUND AND METHODS National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997. RESULTS Mortality among the patients declined from 29.4 per 100 person-years in the first quarter of 1995 to 8.8 per 100 in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit; the inclusion of protease inhibitors in such regimens conferred additional benefit. Patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those insured by Medicare or Medicaid. CONCLUSIONS The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.

Accounting for Unmeasured Population Substructure in Case-Control Studies of Genetic Association Using a Novel Latent-Class Model

We propose a novel latent-class approach to detect and account for population stratification in a case-control study of association between a candidate gene and a disease. In our approach, population substructure is detected and accounted for using data on additional loci that are in linkage equilibrium within subpopulations but have alleles that vary in frequency between subpopulations. We have tested our approach using simulated data based on allele frequencies in 12 short tandem repeat (STR) loci in four populations in Argentina.

Inference on Haplotype Effects in Case-Control Studies Using Unphased Genotype Data

A variety of statistical methods exist for detecting haplotype-disease association through use of genetic data from a case-control study. Since such data often consist of unphased genotypes (resulting in haplotype ambiguity), such statistical methods typically apply the expectation-maximization (EM) algorithm for inference. However, the majority of these methods fail to perform inference on the effect of particular haplotypes or haplotype features on disease risk. Since such inference is valuable, we develop a retrospective likelihood for estimating and testing the effects of specific features of single-nucleotide polymorphism (SNP)-based haplotypes on disease risk using unphased genotype data from a case-control study. Our proposed method has a flexible structure that allows, among other choices, modeling of multiplicative, dominant, and recessive effects of specific haplotype features on disease risk. In addition, our method relaxes the requirement of Hardy-Weinberg equilibrium of haplotype frequencies in case subjects, which is typically required of EM-based haplotype methods. Also, our method easily accommodates missing SNP information. Finally, our method allows for asymptotic, permutation-based, or bootstrap inference. We apply our method to case-control SNP genotype data from the Finland-United States Investigation of Non-Insulin-Dependent Diabetes Mellitus (FUSION) Genetics study and identify two haplotypes that appear to be significantly associated with type 2 diabetes. Using the FUSION data, we assess the accuracy of asymptotic P values by comparing them with P values obtained from a permutation procedure. We also assess the accuracy of asymptotic confidence intervals for relative-risk parameters for haplotype effects, by a simulation study based on the FUSION data.

Cross‐Sectional Study

Cross-sectional studies estimate the distribution of quantities at a certain moment in time. Only one set of observations is taken from each subject in a cross-sectional study. Cross-sectional studies may be used to estimate prevalence of a disease or risk factor, make inferences about the association between variables such as an outcome and explanatory variable, or to make inferences about disease incidence. If population characteristics are constant over time, then analysis of the age distribution of a quantity of interest can describe age-specific incidence. Multiple cross-sectional studies may be used to monitor trends in the distribution of a variable. Cross-sectional prevalence of a transient state early in disease can be used to measure disease incidence. Although cross-sectional studies may reveal suggestive associations between explanatory variables and outcomes, causality cannot usually be inferred from cross-sectional data. Cross-sectional data may also be subject to sampling biases like length-biased sampling or recall bias. Keywords: target population; longitudinal study, explanatory variable; monitoring; disease incidence; retrospective study; cost

Probability of female-to-male transmission of HIV-1 in Thailand

The epidemic of human immunodeficiency virus type 1 (HIV-1) infection in Thailand has allowed an estimate to be made of the probability of female-to-male HIV-1 transmission per sexual contact. In a study of 1115 21-year-old male military conscripts, of whom 77 (6.9%) were HIV-1 seropositive, sex with female prostitutes was identified as the principal mode of HIV-1 transmission. With a mathematical model including data on conscripts age at first sexual contact, frequency of sex with female prostitutes, and province of origin; as well as province-specific HIV-1 seroprevalence of prostitutes, we estimated the probability of HIV-1 transmission per sexual contact to be 0.031 (95% confidence limits [CL] 0.025-0.040). Allowing for random error in the self-reported frequency of contacts, the estimate was 0.056 (95% CL 0.041-0.075). The transmission probability was significantly greater among men with a history of sexually-transmitted diseases. These estimates are substantially higher than analogous estimates made in North America. This high per-act probability of heterosexual transmission helps to explain the rapid spread of HIV-1 in the emerging epidemic in Thailand and perhaps in other countries where HIV-1 transmission is predominantly heterosexual.

Time course of viremia and antibody seroconversion following human immunodeficiency virus exposure

Rational application of diagnostic assays in the management of healthcare workers (HCWs) following occupational exposure is needed to rule out pre-existing human immunodeficiency virus (HIV) infection, detect HIV infection or seroconversion as early as possible in the small proportion individuals who become infected, and to rule out infection in the high proportion of individuals who remain uninfected following occupational exposure to HIV. An understanding of the time course of viremia and seroconversion following HIV exposure is essential in developing recommendations for management of occupational exposure among HCWs. Several data sources that address the timing and dynamics of HIV viremia and seroconversion following primary infection are reviewed. The implications of each data source for management of occupational exposure among HCWs is assessed. Although the majority of infected HCWs seroconvert within 2 months of exposure, the possibility of delayed seroconversion is well established, with approximately 5% of infected HCWs estimated to seroconvert >6 months after exposure. In contrast, the period of viremia (detectable by p24 antigen or RNA assays) preceding antibody seroconversion is consistently brief (1-3 weeks). Animal inoculation studies indicate that a variable period of localized viral replication in lymphoid tissue draining inoculation sites exists prior to systemic viremia and subsequent seroconversion.

Age-associated DNA methylation in pediatric populations

DNA methylation (DNAm) plays diverse roles in human biology, but this dynamic epigenetic mark remains far from fully characterized. Although earlier studies uncovered loci that undergo age-associated DNAm changes in adults, little is known about such changes during childhood. Despite profound DNAm plasticity during embryogenesis, monozygotic twins show indistinguishable childhood methylation, suggesting that DNAm is highly coordinated throughout early development. Here we examine the methylation of 27,578 CpG dinucleotides in peripheral blood DNA from a cross-sectional study of 398 boys, aged 3-17 yr, and find significant age-associated changes in DNAm at 2078 loci. These findings correspond well with pyrosequencing data and replicate in a second pediatric population (N = 78). Moreover, we report a deficit of age-related loci on the X chromosome, a preference for specific nucleotides immediately surrounding the interrogated CpG dinucleotide, and a primary association with developmental and immune ontological functions. Meta-analysis (N = 1158) with two adult populations reveals that despite a significant overlap of age-associated loci, most methylation changes do not follow a lifelong linear pattern due to a threefold to fourfold higher rate of change in children compared with adults; consequently, the vast majority of changes are more accurately modeled as a function of logarithmic age. We therefore conclude that age-related DNAm changes in peripheral blood occur more rapidly during childhood and are imperfectly accounted for by statistical corrections that are linear in age, further suggesting that future DNAm studies should be matched closely for age.

Microdeletions of 3q29 Confer High Risk for Schizophrenia

Schizophrenia (SZ) is a severe psychiatric illness that affects approximately 1% of the population and has a strong genetic underpinning. Recently, genome-wide analysis of copy-number variation (CNV) has implicated rare and de novo events as important in SZ. Here, we report a genome-wide analysis of 245 SZ cases and 490 controls, all of Ashkenazi Jewish descent. Because many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases, with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3-1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, because increasing evidence suggests an overlap of specific rare copy-number variants (CNVs) between autism and SZ. By combining our data with prior CNV studies of SZ and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with SZ (p = 0.02) and an odds ratio estimate of 17 (95% confidence interval: 1.36-1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior SZ family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for SZ susceptibility.

Performance Characteristics of a New Less Sensitive HIV-1 Enzyme Immunoassay for Use in Estimating HIV Seroincidence

Less sensitive (LS) HIV-1 enzyme immunoassays (EIAs) have significantly improved the quantity and quality of HIV surveillance data. The first LS-HIV-1 EIA, the Abbott 3A11-LS, provided reliable incidence data, but the assay required specialized equipment, and the lack of available reagents made testing difficult. This study evaluated the use of an alternate assay, a modified version of the Vironostika HIV-1 EIA (Vironostika-LS), to be used for LS testing. The Vironostika-LS has similar performance characteristics to the Abbott 3A11-LS with additional advantages. This 96-well formatted assay is commonly found in public health laboratories for routine HIV-1 testing and can be used with both serum and dried blood spot specimens. The estimated mean time from seroconversion (defined using a standardized optical density cutoff of 1.0) with the Vironostika-LS was 170 days (95% CI, 145-200 days). When the Vironostika-LS was applied to a matched serum set previously tested with the Abbott 3A11-LS, the Vironostika-LS accurately identified 97% of specimens with recent or long-standing HIV infection. The paper also reports Vironostika-LS quality control guidelines and the results from 3 rounds of proficiency testing.

Marginal analyses of clustered data when cluster size is informative.

We propose a new approach to fitting marginal models to clustered data when cluster size is informative. This approach uses a generalized estimating equation (GEE) that is weighted inversely with the cluster size. We show that our approach is asymptotically equivalent to within-cluster resampling (Hoffman, Sen, and Weinberg, 2001, Biometrika 73, 13-22), a computationally intensive approach in which replicate data sets containing a randomly selected observation from each cluster are analyzed, and the resulting estimates averaged. Using simulated data and an example involving dental health, we show the superior performance of our approach compared to unweighted GEE, the equivalence of our approach with WCR for large sample sizes, and the superior performance of our approach compared with WCR when sample sizes are small.