Search PubMed⌕ Search

Biomedical subjects

M Davidian

Publications and source records attributed to M Davidian.

At least 19 recordsLinked to original sources
PubMed2001

Robust two-stage estimation in hierarchical nonlinear models.

Hierarchical models encompass two sources of variation, namely within and among individuals in the population; thus, it is important to identify outliers that may arise at each sampling level. A two-stage approach to analyzing nonlinear repeated measurements naturally allows parametric modeling of the respective variance structure for the intraindividual random errors and interindividual random effects. We propose a robust two-stage procedure based on Huber's (1981, Robust Statistics) theory of M-estimation to accommodate separately aberrant responses within an experimental unit and subjects deviating from the study population when the usual assumptions of normality are violated. A toxicology study of chronic ozone exposure in rats illustrates the impact of outliers on the population inference and hence the advantage of adopting the robust methodology. The robust weights generated by the two-stage M-estimation process also serve as diagnostics for gauging the relative influence of outliers at each level of the hierarchical model. A practical appeal of our proposal is the computational simplicity since the estimation algorithm may be implemented using standard statistical software with a nonlinear least squares routine and iterative capability.

Air Pollutants↗
PubMed2000

Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus.

Many studies have shown that patients infected with hepatitis C virus (HCV) of genotype 2 have better response to interferon (IFN)-alpha treatment than genotype 1 patients; however, the mechanisms responsible for this difference are not understood. In this study, viral dynamics during high-dose IFN induction treatment were compared between the genotypes. Patients in each group received 10 MU of IFN-alpha2b for 14 days, and HCV RNA levels were frequently determined. Nonlinear fitting, both individually for each patient and using a mixed-effects approach, of the viral kinetic data to a mathematical model of the IFN effect on HCV infection was performed. The antiviral effectiveness of IFN in blocking virus production, the free virion clearance rate, and the HCV-infected cell death rate were all significantly higher for genotype 2 patients than for genotype 1 patients. Thus, the better response rate of patients infected with HCV genotype 2 is multifactorial. This is the first finding of a difference in viral dynamics between subtypes of the same virus and demonstrates the importance of subtype-specific virus-host-drug interactions.

Antiviral Agents↗
PubMed2000

Estimating data transformations in nonlinear mixed effects models.

A routine practice in the analysis of repeated measurement data is to represent individual responses by a mixed effects model on some transformed scale. For example, for pharmacokinetic, growth, and other data, both the response and the regression model are typically transformed to achieve approximate within-individual normality and constant variance on the new scale; however, the choice of transformation is often made subjectively or by default, with adoption of a standard choice such as the log. We propose a mixed effects framework based on the transform-both-sides model, where the transformation is represented by a monotone parametric function and is estimated from the data. For this model, we describe a practical fitting strategy based on approximation of the marginal likelihood. Inference is complicated by the fact that estimation of the transformation requires modification of the usual standard errors for estimators of fixed effects; however, we show that, under conditions relevant to common applications, this complication is asymptotically negligible, allowing straightforward implementation via standard software.

Arginine↗
PubMed2000

Correcting for measurement error in individual-level covariates in nonlinear mixed effects models.

The nonlinear mixed effects model is used to represent data in pharmacokinetics, viral dynamics, and other areas where an objective is to elucidate associations among individual-specific model parameters and covariates; however, covariates may be measured with error. For additive measurement error, we show substitution of mismeasured covariates for true covariates may lead to biased estimators for fixed effects and random effects covariance parameters, while regression calibration may eliminate bias in fixed effects but fail to correct that in covariance parameters. We develop methods to take account of measurement error that correct this bias and may be implemented with standard software, and we demonstrate their utility via simulation and application to data from a study of HIV dynamics.

Biometry↗
PubMed1999

Human immunodeficiency virus type 1-specific cytotoxic T lymphocyte activity is inversely correlated with HIV type 1 viral load in HIV type 1-infected long-term survivors.

HIV-1-specific cytotoxic T cell (CTL) activity has been suggested to correlate with protection from progression to AIDS. We have examined the relationship between HIV-specific CTL activity and maintenance of peripheral blood CD4+ T lymphocyte counts and control of viral load in 17 long-term survivors (LTSs) of HIV-1 infection. Longitudinal analysis indicated that the LTS cohort demonstrated a decreased rate of CD4+ T cell loss (18 cells/mm3/year) compared with typical normal progressors (approximately 60 cells/mm3/year). The majority of the LTSs had detectable, variable, and in some individuals, quite high (>10(4) RNA copies/ml) plasma viral load during the study period. In a cross-sectional analysis, HIV-specific CTL activity to HIV Gag, Pol, and Env proteins was detectable in all 17 LTSs. Simultaneous analysis of HIV-1 Gag-Pol, and Env-specific CTLs and virus load in protease inhibitor-naive individuals showed a significant inverse correlation between Pol-specific CTL activity and plasma HIV-1 RNA levels (p = 0.001). Furthermore, using a mixed linear effects model the combined effects of HIV-1 Pol- and Env-specific CTL activity on the viral load were significantly stronger than the effects of HIV-1 Pol-specific CTL activity alone on predicted virus load. These data suggest that the presence of HIV-1-specific CTL activity in HIV-1-infected long-term survivors is an important component in the effective control of HIV-1 replication.

CD4 Lymphocyte Count↗
PubMed1998

The effect of serial dilution error on calibration inference in immunoassay.

A common practice in immunoassay is the use of sequential dilutions of an initial stock solution of the antigen of interest to obtain standard samples in a desired concentration range. Nonlinear, heteroscedastic regression models are a common framework for analysis, and the usual methods for fitting the model assume that measured responses on the standards are independent. However, the dilution procedure introduces a propagation of random measurement error that may invalidate this assumption. We demonstrate that failure to account for serial dilution error in calibration inference on unknown samples leads to serious inaccuracy of assessments of assay precision such as confidence intervals and precision profiles. Techniques for taking serial dilution error into account based on data from multiple assay runs are discussed and are shown to yield valid calibration inferences.

Algorithms↗
PubMed1998

Laser scanning cytometry quantification of estrogen receptors in breast cancer.

OBJECTIVE: To describe the laser scanning cytometry (LSC) processing and analysis developed for the quantitative analysis of estrogen receptor (ER) content in routine paraffin sections of breast carcinomas. STUDY DESIGN: Histologic sections of archival, paraffin-embedded tissues from 30 breast carcinomas were labeled for ER with fluoresceinated monoclonal antibody. ER expression was quantified by LSC and expressed as percent positive tumor cells and as histogram distributions of receptor expression per cell. Duplicate sections of the same tumors were stained for ER by a conventional immunoperoxidase reaction and percent positive tumor cells counted visually. RESULTS: Percent ER-positive tumor cells by LSC of immunofluorescence-stained sections correlated well with conventional (visual) counts of immunoperoxidase-stained duplicate sections when the latter were categorized as low, intermediate or high percent of positive cells. In addition, the marked variation in relative number of ER binding sites per cell could be quantified by LSC and displayed in histogram distribution. CONCLUSION: LSC measurements are fast and objective and can be carried out on sections of paraffin-embedded tissue after routine processing in the pathology laboratory. In addition, LSC data provide the relative number of ER binding sites per unit of DNA; that may reveal clinically significant skewed distributions or subpopulations of tumor cells.

Breast Neoplasms↗
PubMed1998

Estimating the parameters in the Cox model when covariate variables are measured with error.

The Cox proportional hazards model is commonly used to model survival data as a function of covariates. Because of the measuring mechanism or the nature of the environment, covariates are often measured with error and are not directly observable. A naive approach is to use the observed values of the covariates in the Cox model, which usually produces biased estimates of the true association of interest. An alternative strategy is to take into account the error in measurement, which may be carried out for the Cox model in a number of ways. We examine several such approaches and compare and contrast them through several simulation studies. We introduce a likelihood-based approach, which we refer to as the semiparametric method, and show that this method is an appealing alternative. The methods are applied to analyze the relationship between survival and CD4 count in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Testing homogeneity of intra-run variance parameters in immunoassay.

A common assumption in the analysis of immunoassay data is a similar pattern of within-run variation across runs of the assays. One makes this assumption without formal investigation of its validity, despite the widely acknowledged fact that accurate understanding of intra-run variation is critical to reliable calibration inference. We propose a simple procedure for a formal test of the assumption of the homogeneity of parameters that characterize intra-run variation based on representation of standard curve data from multiple assay runs by a non-linear mixed effects model. We examine the performance of the procedure and investigate the robustness of calibration inference to incorrect assumptions about the pattern of intra-run variation.

Calibration↗
PubMed1997

Calibration inference based on multiple runs of an immunoassay.

Several authors have documented the poor performance of usual large-sample, individual calibration confidence intervals based on a single run of an immunoassay. Inaccuracy of these intervals may be attributed to the paucity of information on model parameters available in a single run. Methods for combining information from multiple runs to estimate assay response variance parameters and to refine characterization of the standard curve for the current run via empirical Bayes techniques have been proposed. We investigate formally the utility of these techniques for improving the quality of routine individual calibration inference.

Bayes Theorem↗
PubMed1996

Adenocarcinoma of the retinal pigment epithelium: a diagnostic and therapeutic challenge.

BACKGROUND: Adenocarcinoma of the retinal pigment epithelium (RPE) is an uncommon intraocular tumor which has been rarely if ever diagnosed prior to enucleation. Our review of the literature suggests that when a melanotic and tuberous-shaped tumor presents in a woman with signs of uveitis one should consider the diagnosis of adenocarcinoma of the RPE. METHODS: We report a case in which a 4.9-mm-tall, mushroom-shaped, moderately reflective melanotic tumor found to be present in a 50-year-old woman. Other findings included a 12 x 10-mm dense transillumination shadow and 270 deg of posterior iris synechiae. With a presumptive diagnosis of uveal melanoma the patient was treated with palladium-103 plaque radiotherapy. Within 6 months she underwent enucleation due to uncontrollable ocular pain and progressive tumor growth. Histopathologic evaluation revealed an adenocarcinoma of the (RPE). RESULTS: Two months after radiotherapy the eye developed acute angle-closure glaucoma, secondary retinal detachment, and a painful scleritis (a result similar to that of Greer, who treated an intraocular adenoma with radiation). Our diagnosis of adenocarcinoma of the RPE was made after enucleation. CONCLUSION: Adenocarcinomas of the RPE are rarely if ever diagnosed on clinical evaluation, should be suspected in women with a melanotic intraocular tumor and uveitis, and may respond poorly to ophthalmic plaque radiotherapy. All reported cases presenting without extrascleral extension have not metastasized.

Adenocarcinoma↗
PubMed1996

Pyrimethamine pharmacokinetics in human immunodeficiency virus-positive patients seropositive for Toxoplasma gondii.

Pyrimethamine pharmacokinetics were studied in 11 human immunodeficiency virus (HIV)-positive patients who were seropositive for exposure to Toxoplasma gondii and were taking zidovudine (AIDS Clinical Trials Group Protocol 102). Pyrimethamine was administered at 50 mg daily for 3 weeks to achieve steady state, and pharmacokinetic profiles were determined after administration of the last dose. Noncompartmental and compartmental analyses were performed. Population pharmacokinetic analysis assuming a one-compartment model yielded the following estimates: area under the 24-h concentration-time curve, 42.7 +/- 12.3 micrograms.h/ml; halflife, 139 +/- 34 h; clearance, 1.28 +/- 0.41 liters/h; volume of distribution, 246 +/- 641; and absorption rate constant, 1.5 +/- 1.3 liters/h. These values are similar to those seen in subjects without HIV infection. Pyrimethamine pharmacokinetics did not differ significantly in those subjects who were intravenous drug users. Adverse effects were noted in 73% of those initially enrolled in this study, leading to discontinuation for 38%. No association was noted between pyrimethamine levels and the incidence of adverse events. No significant differences were seen in zidovudine pharmacokinetic parameters obtained from studies performed before and during treatment with pyrimethamine. In summary, pyrimethamine exhibited pharmacokinetics in HIV-infected patients that were similar to those in non-HIV-infected subjects and it did not alter the pharmacokinetics of zidovudine in these patients.

AIDS-Related Opportunistic Infections↗
PubMed1996

The effect of variance function estimation on nonlinear calibration inference in immunoassay data.

Often with data from immunoassays, the concentration-response relationship is nonlinear and intra-assay response variance is heterogeneous. Estimation of the standard curve is usually based on a nonlinear heteroscedastic regression model for concentration-response, where variance is modeled as a function of mean response and additional variance parameters. This paper discusses calibration inference for immunoassay data which exhibit this nonlinear heteroscedastic mean-variance relationship. An assessment of the effect of variance function estimation in three types of approximate large-sample confidence intervals for unknown concentrations is given by theoretical and empirical investigation and application to two examples. A major finding is that the accuracy of such calibration intervals depends critically on the nature of response variance and the quality with which variance parameters are estimated.

Algorithms↗
PubMed1995

Therapeutic effects of diethylcarbamazine and 3'-azido-3'-deoxythymidine on feline leukemia virus lymphoma formation.

Twenty-four specific pathogen-free kittens were infected with the Rickard strain of feline leukemia virus (FeLVR). The kittens were divided into four equal groups and were orally administered either a high dose of diethylcarbamazine (DECH, 12 mg kg-1), a low dose of diethylcarbamazine (DECL, 3 mg kg-1), 3'-azido-3'-deoxythymidine (AZT, 15 mg kg-1, b.i.d.), or a placebo (250 mg granular dextrose) daily for 10 weeks. Blood was collected at 2-week intervals for complete blood counts (CBC) and flow cytometric analysis (FACS) of peripheral blood lymphocytes (PBL). Plasma was assayed for antibodies to FeLV gp70 and for FeLV p27 antigen using ELISA assays. For FACS analysis, lymphocytes were incubated with monoclonal antibodies to feline Pan T, CD8+, CD4+, and B cell (Anti-Ig) antigens. In the placebo treated cats, FeLVR infection caused an early (2 weeks p.i.) and persistent decrease in leukocyte numbers attributable primarily to a decrease in neutrophil numbers and a secondary lesser decrease in B and CD4+ lymphocyte numbers. The DEC-treated groups showed a delayed but similar leukopenia by 4 weeks p.i. The lymphopenia in the DEC groups (primarily B cells and CD4+ cells) was reversed by 10 weeks p.i., but the neutropenia persisted. AZT treatment inhibited FeLVR-induced lymphopenia but did not prevent a reduction in neutrophil numbers. A marked p27 antigenemia that peaked at 4 weeks p.i. was noted in the placebo treated cats and in most cats (11/12) treated with either dose of DEC. However, AZT significantly inhibited the p27 antigenemia and all cats were negative for p27 antigen between 6 and 10 weeks of treatment. In general, placebo treated cats as well as DECH and DECL cats had low levels of antibody to gp70 throughout the study, suggesting FeLVR-induced immunosuppression. In contrast, significantly higher titers of anti-gp70 antibodies were seen in AZT-treated cats at 6 weeks p.i., and were maintained throughout treatment. Eighteen month survival rates provide efficacy data for AZT as well as both DEC treatment groups. While all placebo treated cats were euthanized by 52 weeks p.i. due to FeLV associated lymphomas with a mean survival time of 35.5 weeks p.i., median survival time of the AZT treated group was > or = 102 weeks p.i., while that of the DECH and DECL groups was 69.7 and 72 weeks p.i., respectively. Thus, DEC as well as AZT therapy delays the development of lymphomas associated with FeLV infection and significantly improves survival.

Animals↗
PubMed1994

Assays for recombinant proteins: a problem in non-linear calibration.

Quantification of protein levels in biological matrices such as serum or plasma frequently relies on the techniques of immunoassay or bioassay. The relevant statistical problem is that of non-linear calibration, where one estimates analyte concentration in an unknown sample from a calibration curve fit to known standard concentrations. This paper discusses a general framework for calibration curve fit to known standard concentrations. This paper discusses a general framework for calibration inference, that of the non-linear mixed effects model. Within this framework, we consider two issues in depth: accurate characterization of intra-assay variation, and the use of empirical Bayes methods in calibration. We show that proper characterization of intra-assay variability requires pooling of information across several assay runs. Simulation work indicates that use of empirical Bayes methods may afford considerable gain in efficiency; one must weigh this gain against practical considerations in the implementation of Bayesian techniques. We illustrate the methods discussed using a cell-based bioassay for the recombinant hormone relaxin.

Bayes Theorem↗