Biomedical subjects

Dean A Follmann

Publications and source records attributed to Dean A Follmann.

8 recordsLinked to original sources

PubMed2005

Genetic polymorphisms of eosinophil-derived neurotoxin and eosinophil cationic protein in tropical pulmonary eosinophilia.

Because eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are critical in the pathogenesis of tropical pulmonary eosinophilia (TPE), we analyzed genetic polymorphisms of both in 181 individuals from southern India with varying clinical manifestations of Wuchereria bancrofti infection (including 26 with TPE). Using haplotype frequency analysis, we identified four known (of nine) and two novel haplotypes for EDN (1, 2, 7, 8, 10, and 11). For ECP, five (of seven known) haplotypes (1-5) were identified. Although we found no significant association between frequencies of EDN and ECP polymorphisms and TPE development, we observed a unique pattern of EDN and ECP polymorphism distribution among this population. Genotype TT at locus 1088 of ECP in one TPE patient was not observed in any other clinical group. Although the EDN and ECP polymorphisms appear unlikely to be associated with the development of TPE, further analyses will be more definitive.

Animals↗

PubMed2004

Effect of chronic cytokine therapy on clonal dynamics in nonhuman primates.

Hematopoietic cytokines such as filgrastim are used extensively to stimulate granulocyte production or to mobilize hematopoietic progenitors into the circulation; however, their effect on more primitive hematopoietic progenitor and stem cells in vivo is unknown, particularly in large animals or humans. In particular, there is concern that chronic therapy with cytokines could result in stem cell exhaustion or clonal dominance; however, direct assessment of the dynamics of individual stem and progenitor cell clones in vivo has not been previously reported. A number of models can be proposed regarding the mechanisms by which the marrow responds to cytokine stimulation, including recruitment of previously quiescent clones, stimulation of proliferation of already active clones, or prevention of apoptosis of more mature progenitors from all clones. Using retroviral marking and comprehensive insertion site tracking of individual stem and progenitor cell clones in 2 rhesus macaques, we analyzed the effect of chronic administration of granulocyte colony-stimulating factor (G-CSF), or a combination of G-CSF plus stem cell factor (SCF). The overall number of contributing clones remained constant, and the relative output from each clone did not change significantly during or following cytokine treatments. These results suggest that individual transduced stem or progenitor cells can contribute to hematopoiesis for prolonged periods, with no evidence for an effect of G-CSF or G-CSF/SCF on the number, the lifespan, or the relative activity of individual stem or progenitor cell clones. These relevant large animal studies are reassuring regarding clinical applications of cytokines and provide new insights into their mechanisms of action.

Animals↗

PubMed2004

Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection.

Studies establishing that intermittent subcutaneous interleukin-2 (IL-2) therapy can lead to substantial CD4 cell increases in many HIV-infected patients have generally been of limited duration. We studied 77 patients participating in active longitudinal studies of subcutaneous IL-2 therapy at our center in order to determine the long-term feasibility of this approach. Following initial induction, patients in each trial were eligible to receive intermittent 5-day cycles of subcutaneous IL-2 treatment at individualized doses and frequencies capable of maintaining CD4 counts at postinduction levels. The mean duration of study participation to date is 5.9 years (range, 1.0-9.3 years). Mean baseline CD4 cell count and CD4 percent values of 0.521 x 10(9)/L (521 cells/microL) and 27% have risen to 1.005 x 10(9)/L (1005 cells/microL) and 38%, respectively, at 90 months. The mean number of subcutaneous IL-2 cycles required to achieve and maintain these increases was 10 cycles (range, 3-29 cycles), and the current mean interval of cycling required to maintain these elevations is 39 months (median, 35 months; range, 2-91 months). We conclude that subcutaneous IL-2 therapy is capable of maintaining CD4 cell increases for an extended period using a remarkably low frequency of intermittent cycling. These observations may contribute to patients' acceptance of subcutaneous IL-2 as a favorable long-term treatment strategy.

Adult↗

PubMed2004

The accelerated biased coin up-and-down design in phase I trials.

The biased coin up-and-down design (BCD) is used to allocate doses in phase I clinical trials. The BCD requires that the treatment response or the toxicity evaluation is observed quickly. In trials with a long treatment evaluation, the BCD will lead to long trial duration because a new patient cannot be enrolled until the preceding patient has completed the evaluation period. We propose a simple method to modify the BCD that will reduce the trial duration without significantly affecting the estimate of the target dose. The idea is to allocate a dose to each patient as he or she arrives based on the toxicity information of the last completed subject. This allows multiple patients to be concurrently under evaluation. A simulation study shows that this modification does not adversely affect the precision of the recommended dose, as estimated by isotonic regression, but it does significantly reduce the total time to complete the study.

Bias↗

PubMed2003

Comparing HLA antigen frequencies between two groups of patients.

For diseases that involve the immune system, the alleles of the human leukocyte antigen (HLA) complex can play a major role. For example, if responsiveness to therapy is immunologically mediated, one would think that responders and non-responders might tend to have different HLA alleles. However, comparing the frequencies between the two groups of patients at each allele can introduce a substantial multiple comparisons problem as the number of alleles is large. This paper proposes an efficient two-stage procedure for identifying alleles that may mediate response. In the first-stage, the distribution of all alleles for the patients are compared to a reference population and a few alleles are selected. These candidate alleles are then compared between the two groups of patients using a modest Bonferroni correction. The two-stage procedure strongly controls the type I error rate as the first-stage selection is statistically independent of the second-stage tests. We analyse a cohort of patients with bone marrow failure who are classified as responders or non-responders to immunosuppressive therapy. Published in 2003 by John Wiley & Sons, Ltd.

Alleles↗

PubMed2002

Regression analysis based on pairwise ordering of patients' clinical histories.

When a medical treatment influences a variety of outcomes, describing the global effect of treatment can be difficult. Traditional approaches specify how treatment affects each separate outcome. This can be done with separate models for each outcome, or by using a combined multivariate model. Describing the overall effect of a treatment thus requires combining these separate effects in some fashion and can be difficult to explain. In this paper, I specify a regression model for use with multiple outcomes where the outcome histories for each pair of patients are ranked. Pairs of patients with different lengths of follow-up are evaluated solely over the common follow-up interval. The logit of the probability that the outcome for patient i is better than that of patient j is assumed to depend on a linear function of the difference of the covariate vectors (for example, treatment indicators) for persons i and j. Thus covariates directly affect the entire clinical history, rather than directly affecting specific outcomes that comprise the history. The idea is that ranking outcomes is more relevant and interpretable than statistically combining separate effects. An estimating equations approach for estimation is described and an example of a clinical trial involving patients with heart failure is provided.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

Parametric and semiparametric approaches to testing for seasonal trend in serial count data.

We present two tests for seasonal trend in monthly incidence data. The first approach uses a penalized likelihood to choose the number of harmonic terms to include in a parametric harmonic model (which includes time trends and autogression as well as seasonal harmonic terms) and then tests for seasonality using a parametric bootstrap test. The second approach uses a semiparametric regression model to test for seasonal trend. In the semiparametric model, the seasonal pattern is modeled nonparametrically, parametric terms are included for autoregressive effects and a linear time trend, and a parametric bootstrap test is used to test for seasonality. For both procedures, a null distribution is generated under a null Poisson model with time trends and autoregression parameters. We apply the methods to skin melanoma incidence rates collected by the surveillance, epidemiology, and end results (SEER) program of the National Cancer Institute, and perform simulation studies to evaluate the type I error rate and power for the two procedures. These simulations suggest that both procedures are alpha-level procedures. In addition, the harmonic model/bootstrap test had similar or larger power than the semiparametric model/bootstrap test for a wide range of alternatives, and the harmonic model/bootstrap test is much easier to implement. Thus, we recommend the harmonic model/bootstrap test for the analysis of seasonal incidence data.

Journal Article↗

PubMed2002

A latent autoregressive model for longitudinal binary data subject to informative missingness.

Longitudinal clinical trials often collect long sequences of binary data. Our application is a recent clinical trial in opiate addicts that examined the effect of a new treatment on repeated binary urine tests to assess opiate use over an extended follow-up. The dataset had two sources of missingness: dropout and intermittent missing observations. The primary endpoint of the study was comparing the marginal probability of a positive urine test over follow-up across treatment arms. We present a latent autoregressive model for longitudinal binary data subject to informative missingness. In this model, a Gaussian autoregressive process is shared between the binary response and missing-data processes, thereby inducing informative missingness. Our approach extends the work of others who have developed models that link the various processes through a shared random effect but do not allow for autocorrelation. We discuss parameter estimation using Monte Carlo EM and demonstrate through simulations that incorporating within-subject autocorrelation through a latent autoregressive process can be very important when longitudinal binary data is subject to informative missingness. We illustrate our new methodology using the opiate clinical trial data.

Algorithms↗