Biomedical subjects

Steven G Self

Publications and source records attributed to Steven G Self.

At least 19 recordsLinked to original sources

PubMed2006

Statistical positivity criteria for the analysis of ELISpot assay data in HIV-1 vaccine trials.

The enzyme-linked immunospot (ELISpot) assay is one of the leading technologies used to measure cellular responses in many settings including HIV vaccine clinical trials. HIV-1-specific effector T lymphocyte responses are considered necessary in the control of infection. Accurate measurement and summary of cellular immune responses are critical to HIV research. ELISpot assay readout is often dichotomized into positive/negative responses according to some pre-specified criteria. Given the increase in the number of replicates used for each stimulation with current assay configurations in the HIV Vaccine Trials Network (HVTN) laboratories, a new approach is now possible. We propose an objective criteria based on a hypothesis-driven method that controls the false positive rate while maintaining sensitivity to each of the antigen-specific responses under study. The new approach is compared to other commonly employed criteria using real and simulated data.

AIDS Vaccines↗

PubMed2006

Peptide selection for human immunodeficiency virus type 1 CTL-based vaccine evaluation.

Dozens of human immunodeficiency virus-type 1 (HIV-1) vaccine candidates specifically designed to elicit cytotoxic T-lymphocyte (CTL) responses have entered the pipeline of clinical trials. Evaluating the immunogenicity and potential efficacy of these HIV-1 vaccine candidates is challenging in the face of the extensive viral genetic diversity of circulating strains. Standardized peptide reagents to define the magnitude and potential breadth of the T-cell response, especially to circulating strains of HIV-1, are needed. For this purpose we developed a biometric approach based on T-cell recognition pattern for defining standardized reagents. Circulating strains in the Los Alamos database were evaluated and standardized algorithms to define all potential T-cell epitopes (PTEs) were generated. While many unique PTEs could be identified, a finite number based upon prevalence of circulating strains in the database, which we define as vaccine-important PTEs (VIPs), were used to select a common standardized panel of HIV-1 peptides for CTL-based vaccine evaluation. The usability of PTE peptide set was manifested by detection of Nef-specific CTL responses in HIV-1 subtype B infections.

AIDS Vaccines↗

PubMed2006

On modeling HIV and T cells in vivo: assessing causal estimators in vaccine trials.

The first efficacy trials--named STEP--of a T cell vaccine against HIV/AIDS began in 2004. The unprecedented structure of these trials raised new modeling and statistical challenges. Is it plausible that memory T cells, as opposed to antibodies, can actually prevent infection? If they fail at prevention, to what extent can they ameliorate disease? And how do we estimate efficacy in a vaccine trial with two primary endpoints, one traditional, one entirely novel (viral load after infection), and where the latter may be influenced by selection bias due to the former? In preparation for the STEP trials, biostatisticians developed novel techniques for estimating a causal effect of a vaccine on viral load, while accounting for post-randomization selection bias. But these techniques have not been tested in biologically plausible scenarios. We introduce new stochastic models of T cell and HIV kinetics, making use of new estimates of the rate that cytotoxic T lymphocytes--CTLs; the so-called killer T cells--can kill HIV-infected cells. Based on these models, we make the surprising discovery that it is not entirely implausible that HIV-specific CTLs might prevent infection--as the designers explicitly acknowledged when they chose the endpoints of the STEP trials. By simulating thousands of trials, we demonstrate that the new statistical methods can correctly identify an efficacious vaccine, while protecting against a false conclusion that the vaccine exacerbates disease. In addition to uncovering a surprising immunological scenario, our results illustrate the utility of mechanistic modeling in biostatistics.

AIDS Vaccines↗

PubMed2006

Statistical evaluation of HIV vaccines in early clinical trials.

The HIV pandemic is a pressing threat to global public health; HIV vaccine development is critical. Clinical evaluation of HIV vaccine candidates differs from the standard therapeutics trial framework primarily due to the fact that healthy individuals are studied. We present an early stage evaluation program developed for the HIV Vaccine Trials Network (HVTN) motivated by characteristics unique to the vaccine setting. The program consists of 3 prototypical stages (Phase I, Ib, II) that provide a unified yet flexible approach to the safety and immunogenicity evaluation of diverse vaccine regimens. The goal of these early trials is to narrow the number of candidate vaccines to the most promising candidates worthy of further study in efficacy trials.

AIDS Vaccines↗

PubMed2006

The clustering of regression models method with applications in gene expression data.

Identification of differentially expressed genes and clustering of genes are two important and complementary objectives addressed with gene expression data. For the differential expression question, many "per-gene" analytic methods have been proposed. These methods can generally be characterized as using a regression function to independently model the observations for each gene; various adjustments for multiplicity are then used to interpret the statistical significance of these per-gene regression models over the collection of genes analyzed. Motivated by this common structure of per-gene models, we proposed a new model-based clustering method--the clustering of regression models method, which groups genes that share a similar relationship to the covariate(s). This method provides a unified approach for a family of clustering procedures and can be applied for data collected with various experimental designs. In addition, when combined with per-gene methods for assessing differential expression that employ the same regression modeling structure, an integrated framework for the analysis of microarray data is obtained. The proposed methodology was applied to two microarray data sets, one from a breast cancer study and the other from a yeast cell cycle study.

Biometry↗

PubMed2006

Chromosomal instability in Barrett's esophagus is related to telomere shortening.

Barrett's esophagus is a useful model for the study of carcinogenesis, as the metaplastic columnar epithelium that replaces squamous esophageal epithelium is at elevated risk for development of adenocarcinoma. We examined telomere length and chromosomal instability (CIN) in Barrett's esophagus biopsies using fluorescence in situ hybridization. To study CIN, we selected centromere and locus-specific arm probes to chromosomes 17/17p (p53), 11/11q (cyclin D1), and 9/9p (p16 INK4A), loci reported to be involved in early stages of Barrett's esophagus neoplasia. Telomere shortening was observed in Barrett's esophagus epithelium at all histologic grades, whereas CIN was highest in biopsies with dysplastic changes; there was, however, considerable heterogeneity between patients in each variable. Alterations on chromosome 17 were strongly correlated with telomere length (r = 0.55; P < 0.0001) and loss of the 17p arm signal was the most common event. CIN on chromosome 11 was also associated with telomere shortening (r =0.3; P = 0.05), although 11q arm gains were most common. On chromosome 9p, arm losses were the most common finding, but chromosome 9 CIN was not strongly correlated with telomere length. We conclude that CIN is related to telomere shortening in Barrett's esophagus but varies by chromosome. Whether instability is manifested as loss or gain seems to be influenced by the chromosomal loci involved. Because telomere shortening and CIN are early events in Barrett's esophagus neoplastic progression and are highly variable among patients, it will be important to determine whether they identify a subset of patients that is at risk for more rapid neoplastic evolution.

Adenocarcinoma↗

PubMed2005

Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial.

BACKGROUND: An objective of the first efficacy trial of a candidate vaccine containing recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein 120 (rgp120) antigens was to assess correlations between antibody responses to rgp120 and the incidence of HIV-1 infection. METHODS: Within the randomized trial (for vaccinees, n=3598; for placebo recipients, n=1805), binding and neutralizing antibody responses to rgp120 were quantitated. A case-cohort design was used to study correlations between antibody levels and HIV-1 incidence. RESULTS: Peak antibody levels were significantly inversely correlated with HIV-1 incidence. The relative risk (RR) of infection was 0.63 (95% confidence interval, 0.45-0.89) per log(10) higher neutralization titer against HIV-1(MN), and the RRs of infection for second-, third-, and fourth-quartile responses of antibody blocking of gp120 binding to soluble CD4 versus first-quartile responses (the lowest responses) were 0.35, 0.28, and 0.22, respectively. CONCLUSIONS: Despite inducing a complex, robust immune response, the vaccine was unable to reduce the incidence of HIV-1. Two interpretations of the correlative results are that the levels of antibodies (i) caused both an increased (low responders) and decreased (high responders) risk of HIV-1 acquisition or (ii) represented a correlate of susceptibility to HIV-1 but had no causal effect on susceptibility. Although the data cannot definitively discriminate between these 2 explanations, (ii) appears to be more likely.

AIDS Vaccines↗

PubMed2005

Denoising array-based comparative genomic hybridization data using wavelets.

Array-based comparative genomic hybridization (array-CGH) provides a high-throughput, high-resolution method to measure relative changes in DNA copy number simultaneously at thousands of genomic loci. Typically, these measurements are reported and displayed linearly on chromosome maps, and gains and losses are detected as deviations from normal diploid cells. We propose that one may consider denoising the data to uncover the true copy number changes before drawing inferences on the patterns of aberrations in the samples. Nonparametric techniques are particularly suitable for data denoising as they do not impose a parametric model in finding structures in the data. In this paper, we employ wavelets to denoise the data as wavelets have sound theoretical properties and a fast computational algorithm, and are particularly well suited for handling the abrupt changes seen in array-CGH data. A simulation study shows that denoising data prior to testing can achieve greater power in detecting the aberrant spot than using the raw data without denoising. Finally, we illustrate the method on two array-CGH data sets.

Breast Neoplasms↗

PubMed2005

How many human immunodeficiency virus type 1-infected target cells can a cytotoxic T-lymphocyte kill?

The antiviral role of CD8+ cytotoxic T lymphocytes (CTLs) in human immunodeficiency virus type 1 (HIV-1) infection is poorly understood. Specifically, the degree to which CTLs reduce viral replication by killing HIV-1-infected cells in vivo is not known. Here we employ mathematical models of the infection process and CTL action to estimate the rate that CTLs can kill HIV-1-infected cells from in vitro and in vivo data. Our estimates, which are surprisingly consistent considering the disparities between the two experimental systems, demonstrate that on average CTLs can kill from 0.7 to 3 infected target cells per day, with the variability in this figure due to epitope specificity or other factors. These results are compatible with the observed decline in viremia after primary infection being primarily a consequence of CTL activity and have interesting implications for vaccine design.

Cell Line↗

PubMed2005

[Randomized trial of breast self-examination in 266,064 women in Shanghai].

OBJECTIVE: A randomized trial of breast self-examination (BSE) program was carried out to evaluate whether the intensive BSE can reduce the death number of women from breast cancer. METHODS: A total of 266,064 women (age of 30 to 64 years) associated with 519 textile factories in Shanghai had been randomly assigned to a BSE instruction group (132,979 women) or a control group (133,085 women) since 1989. Initial instruction in BSE group included demonstration of proper palpation techniques. It was followed by 2 reinforcement sessions during the subsequent 4 years including video shows, BSE instruction sessions and BSE practice under medical supervision. These activities were continued for 5 years. Attendance at all events was recorded. The cohort was followed through July 2000 for development of breast diseases, and the breast cancer cases were followed up through 2001 for vital status. The data analysis methods used included Kaplan-Meier plots, Log-rank test and Cox modeling. RESULTS: Among women under instruction, 864 breast cancers were detected and 133 breast cancer deaths occurred, and 896 breast cancers were detected and 130 deaths recorded in the control group. The tumor size (P = 0.07), TNM stage (P = 0.39) and cumulative breast cancer mortality rate (P = 0.72) were not significantly different between the 2 groups. However, more and smaller fibroadenomas were detected in the instruction group than in the control group (P < 0.01). CONCLUSION: Intensive instruction in BSE can not reduce mortality rate of breast cancer, but more and smaller benign breast lumps can be detected.

Adult↗

PubMed2004

Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors.

Naturally arising CD25+ CD4+ regulatory T cells (TR) play an important role in the prevention of autoimmunity. TCR specificity is thought to play a critical role in TR development and function, but the repertoire and specificity of TR TCRs remain largely unknown. We find by sequencing of TRAV14 (Valpha2) TCRalpha chains associated with a transgenic TCRbeta chain that the TRand CD25- CD4+ TCR repertoires are similarly diverse, yet only partially overlapping. Retroviral expression of TCRalpha genes in TCR transgenic RAG-deficient T cells revealed that a high frequency of TCRs derived from CD25+ but not CD25- CD4+ T cells confers the ability to rapidly expand upon transfer into a lymphopenic host. Thus, these data show that a large proportion of naturally arising TR have substantially more efficient interactions with MHC class II bound peptides from the peripheral self than CD25- T cells.

Animals↗

PubMed2004

Statistical considerations for the design and analysis of the ELISpot assay in HIV-1 vaccine trials.

Effector T lymphocyte responses are considered critical for controlling human immunodeficiency virus type-1 (HIV-1) infection. The enzyme-linked immunospot (ELISpot) assay has emerged as a primary means of assessing HIV-specific T cell responses, and the development of objective methods that distinguish positive and negative ELISpot responses while properly controlling the rate of false positives is critical. In this paper, we consider several statistical methods that are helpful in defining such a positive criterion. Simulation results under a variety of scenarios suggest that a permutation-based criterion using a resampling adjustment for multiple comparisons yields the desired false positive rate while remaining competitive with other potential criteria in terms of sensitivity. These results also provide guidance on the effect of the number of experimental and negative control replicate wells on assay sensitivity. Application of different potential positive criteria using ELISpot assay results from IFN-gamma-secreting T cells of HIV-1 seropositive and seronegative donors confirmed several of the results obtained under simulation. Our findings support the application of statistically-based positive criteria such as the permutation-based resampling approach in assessing HIV vaccine-induced T cell responses. Moreover, the proposed methods have potential utility in related HIV immunopathogenesis studies and in non-HIV clinical vaccine trials.

AIDS Serodiagnosis↗

PubMed2004

On simulating strongly-interacting, stochastic population models.

Simulating strongly-interacting biological populations over many orders-of-magnitude can be challenging even on fast modern computers. Here we describe a regime-switching technique that can speed up simulations from stochastic models by large factors, while retaining third-order accuracy at each time-step. We apply it to an elementary model of the immune response to an infectious organism.

Computer Simulation↗

PubMed2004

On simulating strongly interacting, stochastic population models. II. Multiple compartments.

In Wick and Stelf [Math. Biosci. 187 (2004) 1], we showed how to simulate a pair of strongly interacting biological populations evolving stochastically over many orders-of-magnitude. Here we generalize the method to any (finite) number of compartments; transitions including births, deaths, progression through life-stages, and mitoses; and arbitrary rate functions. We illustrate the technique for a seven-compartment model of the cellular immune response to a viral infection.

Animals↗

PubMed2004

Endpoints in vaccine trials.

In this paper we discuss statistical considerations regarding endpoints in preventive vaccine trials. Brief discussion is given to preclinical, Phase I, and Phase II trials, with the bulk of attention paid to endpoint choice and analysis in Phase III efficacy trials. In addition to traditional efficacy measures of vaccine effects for immunized individuals, consideration is given to waning, strain specific efficacy, correlates of protective immunity, postinfection endpoints, and cluster randomized trials.

Clinical Trials as Topic↗

PubMed2003

On the analysis of viral load endpoints in HIV vaccine trials.

First generation HIV vaccines are not likely to provide complete protection from HIV-1 infection. Therefore, it is important to assess a vaccine's effect on disease progression and infectiousness of infected vaccinees in an efficacy trial; however, direct assessment of such vaccine effects is not feasible within current trial designs. Viral load in HIV-infected individuals correlates with infectiousness and disease progression in a natural history setting, and thus is a reasonable candidate for a surrogate outcome in vaccine efficacy trials. We consider comparisons of viral load of infected vaccinees to that of infected trial participants in the control group. Dramatic differences in viral loads between these groups would suggest a vaccine effect on disease progression. However, modest differences, even if statistically significant, could be consistent with an imperfect vaccine effect on susceptibility to infection and not an effect on disease progression, that is, a selection effect of the vaccine. Thus, the usual statistical tests for no difference between groups do not test the biologically and clinically relevant hypothesis. We propose a model for the possible selective effects of a vaccine and develop several test statistics for assessing a direct effect of the vaccine on viral load given this selection model. Finite sample properties of these tests are evaluated using computer simulations.

AIDS Vaccines↗

PubMed2003

What constitutes efficacy for a human immunodeficiency virus vaccine that ameliorates viremia: issues involving surrogate end points in phase 3 trials.

Initial human immunodeficiency virus (HIV) vaccines are unlikely to prevent acquisition of HIV in all recipients. Moreover, several HIV vaccines are under evaluation that are designed to reduce viremia after acquisition of infection. Such vaccines could provide important benefits to delay HIV progression and to reduce transmission. The decision to license a vaccine on the basis of observed effects on virus load and other postinfection surrogate end points in an efficacy trial is complicated by uncertainty about whether the vaccine effects will persist and reliably predict clinical effects, and by the challenge in interpreting the data posed by treatment of some seroconverters with antiretroviral drugs. Here, we evaluate how analyses of certain surrogate end points can be used for inferring clinically significant vaccine effects and propose end points that could be evaluated in efficacy trials to support licensure. The assessment suggests that a vaccine demonstrating moderately durable effects to delay therapy and to ameliorate viremia merits consideration for licensure.

AIDS Vaccines↗

PubMed2002

What's the matter with HIV-directed killer T cells?

That HIV-specific cytotoxic T-lymphocytes (CTLs) might be defective in some way has stimulated much controversy and research. We use mathematical models to explore the predictions of two competing CTL-defect theories: "defective memory" and "defective activation". We discuss whether these models are consistent with adoptive-transfer experiments in HIV-infected patients and vaccine trials in simian immunodeficiency virus (SIV)-infected monkeys. Finally, we describe experimental tests that could decide among these two theories and a competitor: CTL exhaustion.

Adoptive Transfer↗