Biomedical subjects

Amita K Manatunga

Publications and source records attributed to Amita K Manatunga.

15 recordsLinked to original sources

PubMed2007

Improving point predictions of random effects for subjects at high risk.

The prediction of random effects corresponding to subject-specific characteristics (e.g. means or rates of change) can be very useful in medical and epidemiologic research. At times, one may be most interested in obtaining accurate and/or precise predictions for subjects whose characteristic places them in a tail of the distribution. While the typical posterior mean predictor dominates others in terms of overall mean squared error of prediction (MSEP), its tendency to 'overshrink' has motivated research into alternatives emphasizing other criteria. Here, we specifically target MSEP within a certain region (e.g. above a known cut-off for high risk or a specified percentile of the random effect distribution), and we consider minimizing this quantity with and without constraints on overall MSEP efficiency. We use the normal-theory random intercept model to derive prediction methods with potential to yield markedly better performance for subjects in the specified region, given a well-controlled and (if desired) modest concession of overall MSEP. Criteria geared toward classification as well as overall and regional prediction unbiasedness are also provided. We evaluate the proposed techniques and illustrate them using repeated measures data on fasting blood glucose from type 2 diabetes patients. A simulation study verifies that theoretical properties and relative performances of the proposed predictors are essentially maintained when calculating them in practice based on estimated mixed linear model parameters. Straightforward extensions to incorporate covariates and additional random effects are briefly outlined.

Bias↗

PubMed2007

Non-parametric estimation for baseline hazards function and covariate effects with time-dependent covariates.

Often in many biomedical and epidemiologic studies, estimating hazards function is of interest. The Breslow's estimator is commonly used for estimating the integrated baseline hazard, but this estimator requires the functional form of covariate effects to be correctly specified. It is generally difficult to identify the true functional form of covariate effects in the presence of time-dependent covariates. To provide a complementary method to the traditional proportional hazard model, we propose a tree-type method which enables simultaneously estimating both baseline hazards function and the effects of time-dependent covariates. Our interest will be focused on exploring the potential data structures rather than formal hypothesis testing. The proposed method approximates the baseline hazards and covariate effects with step-functions. The jump points in time and in covariate space are searched via an algorithm based on the improvement of the full log-likelihood function. In contrast to most other estimating methods, the proposed method estimates the hazards function rather than integrated hazards. The method is applied to model the risk of withdrawal in a clinical trial that evaluates the anti-depression treatment in preventing the development of clinical depression. Finally, the performance of the method is evaluated by several simulation studies.

Algorithms↗

PubMed2006

Validity of self-reported menstrual cycle length.

PURPOSE: Self-reported menstrual cycle length has been associated with host and environmental factors and chronic disease risk. The purpose of this study is to evaluate the validity of self-reported cycle length. METHODS: The authors assessed the agreement between a woman's self-reported "usual" cycle length at study onset with the mean of her observed cycle lengths from prospective daily diaries for 398 women aged 19 to 41 years in the Mount Sinai Study of Women Office Workers (1990 to 1994). RESULTS: Forty-three percent of women self-reported usual cycle lengths more than 2 days different from their mean length. When self-reported cycle length was categorized (<26, 26 to 35, and >35 days) and compared with mean cycle length, 21% of women were misclassified. Women who were older, married, and with higher income were more likely to have accurately reported their menstrual cycle length. Women who had short or long mean cycle lengths (lowest and highest quintile of length) were less likely to self-report accurately, and accuracy decreased monotonically with increasing cycle variability. CONCLUSIONS: These findings show considerable measurement error in self-reported cycle length, as well as describe population subgroups that report menstrual cycle length with the greatest accuracy.

Adult↗

PubMed2006

Menstrual cycle characteristics: associations with fertility and spontaneous abortion.

BACKGROUND: Epidemiologists often use menstrual cycle patterns as indicators of endocrine function in environmental and occupational studies, yet few studies have considered whether menstrual cycle characteristics are associated with fertility or pregnancy outcome. METHODS: We prospectively studied 470 women to determine whether cycle length or bleed length were associated with fertility or spontaneous abortion. Women completed daily diaries with information on menstrual bleeding, intercourse, birth control use, and covariates. For each menstrual cycle, women collected at least 2 urine samples, which were assayed for human chorionic gonadotropin to define early pregnancies. Women were followed for 1 year or until the end of a clinical pregnancy. RESULTS: Cycles with lengths of 30 to 31 days preceded cycles with the highest fecundity. Shorter cycles were less likely to be followed by conception (fecundity ratio [FR] = 0.6; 95% confidence interval [CI] = 0.4-1.0). Compared with 30- to 31-day cycles, conceptions after shorter and longer cycles were more likely to be spontaneously aborted (for shorter cycles, odds ratio [OR] = 3.0 [95% CI = 0.9-9.6] and for longer cycles, OR = 3.0 [0.9-10.6]). Cycles with 5 days of menstrual bleeding had the highest fecundity. Cycles with up to 4 days of bleeding had lower fecundity (for bleed lengths of 4 days, FR = 0.5 [0.3-0.8] and for bleed lengths less than 4 days, FR = 0.6 [0.3-0.9]). Spontaneous abortion was less likely after bleeds greater than 5 days (OR = 0.4 [0.1-1.1]) when compared with 5-day bleeds. CONCLUSIONS: Menstrual cycle characteristics appear to be associated with fertility and spontaneous abortion.

Abortion, Spontaneous↗

PubMed2006

A double-blind, multicenter, parallel-group study of paroxetine, desipramine, or placebo in breast cancer patients (stages I, II, III, and IV) with major depression.

OBJECTIVE: This study compared the efficacy and safety of paroxetine and desipramine with those of placebo in the treatment of depressive disorders in adult women with breast cancer, stages I-IV. METHOD: In a double-blind, placebo-controlled study, 35 female outpatients with breast cancer and DSM-III-R major depression or adjustment disorder with depressed mood were randomly assigned to treatment with paroxetine (N=13), desipramine (N=11), or placebo (N=11) for 6 weeks. Primary efficacy was assessed by change from baseline in score on the 21-item Hamilton Rating Scale for Depression (HAM-D), and the secondary outcome measure was change from baseline in the Clinical Global Impressions-Severity of Illness scale (CGI-S) score. RESULTS: Mean changes in the total HAM-D and CGI-S scores from baseline to 6-week endpoint for the paroxetine and desipramine groups were not significantly different than those for the placebo-treated group. An unusually high rate of response (defined as >or=50% improvement in the HAM-D score) in the placebo group was observed (55% [N=6]); adverse events precipitated patient discontinuation in the active treatment groups (9% [N=1] for desipramine, 15% [N=2] for paroxetine) similar to that in the placebo-treated patients (18% [N=2]). Improvement on symptom dimensions within the HAM-D and Hamilton Rating Scale for Anxiety (depressive, anxiety, cognitive, neurovegetative, or somatic) was also similar between groups. CONCLUSION: The small number of women in this study most likely contributed to the lack of observed differences in efficacy observed during the 6 weeks of treatment. Randomized, placebo-controlled trials of adequate power seeking to determine efficacy of antidepressants in the United States for the treatment of women with breast cancer and comorbid depression remain of paramount importance.

Adult↗

PubMed2005

Modeling menstrual cycle length using a mixture distribution.

In reproductive health studies, epidemiologists are often interested in examining the effects of covariates on menstrual cycle length which is a convenient, noninvasive measure of women's ovarian and reproductive function. Previous literature (Harlow and Zeger, 1991) suggests that the distribution of cycle length is a mixture of a major symmetric distribution and a component featuring a long right tail. Motivated by the shape of this marginal distribution, we propose a mixture distribution for cycle length, representing standard cycles from a Normal distribution and nonstandard cycles from a shifted Weibull distribution. The parameters are estimated using an estimating equation derived from the score function of an independence working model. The fitted mixture distribution agrees well with the distribution estimated using nonparametric approaches. We propose two measures to help determine whether a cycle is standard or nonstandard, developing tools necessary to identify characteristics of the menstrual cycles that are biologically indicative of ovarian dysfunction. We model the effect of a woman's age on the mean and variation of both standard and nonstandard cycle lengths using multiple measurements of women.

Adult↗

PubMed2005

CYP17 genotype predicts serum hormone levels among pre-menopausal women.

BACKGROUND: CYP17, which encodes cytochrome P450c17alpha, mediates both steroid 17alpha-hydroxylase and 17,20-lyase activities, and is essential for the production of glucocorticoids and sex steroids. There is evidence that a common polymorphism in CYP17 (T27C) is associated with estrogen levels, making it a potential marker of disease risk. METHODS: This is the first study to examine the relationship between CYP17 and estradiol (E2) using serum sampled exclusively from the early follicular phase of the menstrual cycle. We assessed the relationship between CYP17 and serum hormone levels, menstrual cycle length, bleed length, and age at menarche in 164 pre-menopausal women. RESULTS: Among women with body mass index (BMI) < or =25 kg/m2, those with the TC and CC genotypes had 19 and 42% higher E2 (P for trend 0.007) and 14 and 30% higher dehydroepiandrosterone sulphate respectively (P for trend 0.10) than women with the TT genotype. Androstenedione levels did not differ between genotypes. Among women with BMI >25 kg/m2, hormone levels did not differ by genotype. Women with the C allele were also more likely to have menstrual cycle lengths <27 days [odds ratio (OR) for TC=2.36, 95% confidence interval (CI)=1.24-4.52; OR for CC=5.59, 95% CI=1.53-20.43 compared to TT]. CYP17 genotype was not associated with menstrual bleed length or age at menarche. CONCLUSION: The CYP17 T27C polymorphism may be a marker of endocrine function.

Adolescent↗

PubMed2005

Modeling the agreement of discrete bivariate survival times using kappa coefficient.

Using local kappa coefficients, we develop a method to assess the agreement between two discrete survival times that are measured on the same subject by different raters or methods. We model the marginal distributions for the two event times and local kappa coefficients in terms of covariates. An estimating equation is used for modeling the marginal distributions and a pseudo-likelihood procedure is used to estimate the parameters in the kappa model. The performance of the estimation procedure is examined through simulations. The proposed method can be extended to multivariate discrete survival distributions.

Models, Statistical↗

PubMed2005

Depressive symptoms and viral clearance in patients receiving interferon-alpha and ribavirin for hepatitis C.

Interferon (IFN)-alpha plus ribavirin is an effective treatment for hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depression has been linked to a worse outcome in multiple medical disorders including viral illnesses. We examined whether increased symptoms of depression during IFN-alpha/ribavirin therapy were associated with a reduced treatment response as assessed by clearance of HCV. Depressive symptoms were evaluated in 102 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of pegylated IFN-alpha-2b plus ribavirin therapy using the Zung self-rating depression scale (SDS). Viral clearance was determined at 24 weeks by polymerase chain reaction (PCR). Only 34% of subjects (10 out of 29) with a 20-point or greater increase in SDS Index score were HCV PCR negative at 24 weeks, compared to 59% (24 out of 41) of patients with a 10-19 point increase in SDS Index and 69% (22 out of 32) of patients with a less than 10 point increase (chi2=7.6, df=2, p <0.05). In addition, a 20-point or greater increase in SDS Index score during IFN-alpha/ribavirin therapy significantly predicted failure to clear virus when considered alone [crude odds ratio (OR), 3.2; 95% confidence interval (CI), 1.3-8.0; p <0.01] or when controlling for other factors that affected IFN-alpha treatment response (adjusted OR, 3.6; 95% CI, 1.3-9.5; p=0.01). These preliminary findings suggest that individuals who experience significant increases in depressive symptoms during IFN-alpha/ribavirin therapy may be less likely to clear virus, highlighting the importance of identifying and treating depressive symptoms in this patient population.

Adult↗

PubMed2005

MSurvPow: a FORTRAN program to calculate the sample size and power for cluster-randomized clinical trials with survival outcomes.

Manatunga and Chen [A.K. Manatunga, S. Chen, Sample size estimation for survival outcomes in cluster-randomized studies with small cluster sizes, Biometrics 56 (2000) 616-621] proposed a method to estimate sample size and power for cluster-randomized studies where the primary outcome variable was survival time. The sample size formula was constructed by considering a bivariate marginal distribution (Clayton-Oakes model) with univariate exponential marginal distributions. In this paper, a user-friendly FORTRAN 90 program was provided to implement this method and a simple example was used to illustrate the features of the program.

Cluster Analysis↗

PubMed2004

Modelling relative survival using transformation methods.

Patient survival is often assessed as a measure of effectiveness of treatment in cancer clinical trials. The relative survival rate is a measure of patient survival corrected for the effect of other causes of death. We incorporate an additive hazards model for the overall force of mortality focusing attention on the form of the underlying disease process. Transformation models for the cause-specific hazard rate describing the disease process are considered. We demonstrate a method for estimating the transformation parameter providing insight into the appropriate choice of model structure. The models include the additive and multiplicative structures as special cases. We write the models in the generalized linear model framework and demonstrate ease of fitting via existing statistical software. The methodology is applied to a Hodgkin's disease data set to assess the effect of clinical trial results on population survival. Our analysis concludes that the multiplicative structure provides a more appropriate description of the data as compared to the additive structure.

Clinical Trials as Topic↗

PubMed2002

Intensive short courses in biostatistics for fellows and physicians.

At both of our universities we teach (with colleagues) introductory courses in statistics for fellows and physicians. We do not expect that those taking these courses will be able to do their own statistical work, but rather the intention is for them to 'learn the language' and to facilitate future collaboration. Basic principles of study design are introduced in the courses, as well as some of the most common statistical procedures. We will discuss the factors (what works and what does not) that may contribute to a successful course, a comparison to other courses, and our self-evaluation strategy. Finally, we will cover the financial arrangements that we have made when teaching these courses.

Biometry↗

PubMed2002

Platelet activation and secretion in patients with major depression, thoracic aortic atherosclerosis, or renal dialysis treatment.

Relatively little is known concerning the magnitude of alterations of platelet activation and secretion markers of patients with major depression when compared to patients at increased risk for, or with current, clinically significant atherosclerosis. Markers of in vivo platelet stimulation and secretion were measured under basal conditions in normal comparison subjects (n = 12) and three patient groups: patients diagnosed with DSM-IV major depression (n = 15), dialysis-dependent patients (n = 12), and patients with severe thoracic aortic atherosclerosis (n = 10). In comparison to normal comparison subjects, depressed patients and patients with thoracic aortic atherosclerosis exhibited the greatest platelet stimulation as detected by increased anti-LIBS platelet binding. Dialysis-dependent patients exhibited the highest plasma concentrations of the renally-excreted platelet-specific secretion protein, beta-thromboglobulin. This study extends previous observations of increased platelet activation in patients with major depression and documents similar alterations in patients with transesophageal echocardiography (TEE)-documented thoracic aortic atherosclerosis. Future studies will determine whether the magnitude of platelet stimulation and secretion in patients with comorbid depression and atherosclerotic aortic disease is greater than that observed in nondepressed patients with atherosclerotic aortic disease or major depression alone. These findings provide further evidence for either increased platelet activation and/or intrinsic heightened platelet reactivity as one of the biological substrates underlying the increased risk of depressed patients for cardiovascular disease.

Adult↗

PubMedDate not supplied

The diagnosis of major depression in patients with cancer: a comparative approach.

Depressive symptoms not only impair quality of life in cancer patients but constitute an independent risk factor for increased mortality. In order to accurately and efficiently identify depression in cancer patients, the authors developed a biostatistical strategy to identify items of the 21-item, observer-rated Hamilton Rating Scale for Depression (Ham-D) that would optimize the diagnosis of depression among cancer patients. Exhibiting a relatively high sensitivity and specificity, our most optimal diagnostic tool contained six Ham-D items (late insomnia, agitation, psychic anxiety, diurnal mood variation, depressed mood, and genital symptoms). This study may serve as a prototype to generate valid instruments accurate for the diagnosis of major depression in other populations of cancer patients.

Adult↗

PubMedDate not supplied

Are plasma citrulline and glutamine biomarkers of intestinal absorptive function in patients with short bowel syndrome?

Sensitive biomarkers for intestinal absorptive function would be clinically useful in short bowel syndrome (SBS). Citrulline (Cit) is a product of the metabolism of glutamine (Gln) and derived amino acids by enterocytes. Cit is produced almost exclusively by the gut, which is also a major site of Gln metabolism. The goals of this study were to examine whether plasma Cit and Gln concentrations are biomarkers of residual small intestinal length and nutrient absorptive functions in adult SBS patients followed prospectively. We studied 24 stable adults with severe SBS receiving chronic parenteral nutrition (PN) in a double-blind, randomized trial of individualized dietary modification +/- recombinant human growth hormone (GH). During a baseline week, intestinal absorption studies (% absorption of fluid, kcal, nitrogen, fat, carbohydrate, sodium, phosphorus, and magnesium) were performed and concomitant plasma Cit and Gln concentrations determined. Individualized dietary modification and treatment with subcutaneous injection of placebo (n = 9) or GH (0.1 mg/kg daily x 21 days, then 3 times/week; n = 15) were then begun. PN weaning was initiated after week 4 and continued as tolerated for 24 weeks. Repeat plasma amino acid determination and nutrient absorption studies were performed at weeks 4 and 12. Residual small bowel length at baseline was positively correlated with baseline plasma Cit (r = 0.467; p = .028). However, no significant correlations between absolute Cit or Gln concentrations and the percent absorption of nutrient substrates at any time point were observed. Similarly, no correlation between the change in Cit or GLN concentration and the change in % nutrient absorption was observed (baseline vs weeks 4 and 12, respectively). By weeks 12 and 24, 7 and 13 subjects were weaned completely from PN, respectively. However, baseline plasma Cit or Gln did not predict PN weaning at these time points. We concluded that plasma Cit (but not Gln) concentrations appeared to be an indicator of small intestinal length in adult SBS. However, neither plasma Cit nor Gln was a biomarker for intestinal absorptive function in this cohort of patients with SBS.

Biomarkers↗