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Biomedical subjects

V M Chinchilli

Publications and source records attributed to V M Chinchilli.

At least 73 records · Page 4Linked to original sources
PubMed1995

Nonadditive developmental toxicity in mixtures of trichloroethylene, Di(2-ethylhexyl) phthalate, and heptachlor in a 5 x 5 x 5 design.

In order to identify nonadditive effects on development, three compounds were combined using five dosages of each agent (a 5 x 5 x 5 full-bacterial design). Trichloroethylene (TCE), di(2-ethylhexyl) phthalate (DEHP), and heptachlor (HEPT), in corn oil, were administered by gavage to Fischer-344 rats on Gestation Days 6-15. Dose levels were 0, 10.1, 32, 101, and 320 mg/kg/day for TCE; 0, 24.7, 78, 247, and 780 mg/kg/day for DEHP; and 0, 0.25, 0.8, 2.5, and 8 mg/kg/day for HEPT. The dams were allowed to deliver and their pups were weighed and examined postnatally. Maternal death showed no main effects but DEHP and HEPT were synergistic. For maternal weight gain on Gestational Days 6-8, main effects for all three agents were observed, as well as 6-8 main effects for all three agents were observed, as well as TCE-DEHP synergism, and DEHP-HEPT antagonism. Maternal weight gain on Gestational Days 6-20 adjusted for litter weight showed main effects for TCE and HEPT, but no interactions. Main effects for all three agents were evident for full-litter resorptions and prenatal loss. The HEPT main effects were unexpected and were interpreted as reflecting potentiation by HEPT of the other agents. For full-litter loss, the TCE-HEPT and DEHP-HEPT interactions were antagonistic, perhaps due to a "ceiling" effect. For prenatal loss, the TCE-DEHP interaction was synergistic. Postnatal loss showed DEHP and HEPT main effects but no interaction. Analysis of pup weights on Day 1 revealed TCE and DEHP main effects and DEHP-HEPT antagonism; on Day 6, DEHP and HEPT main effects, DEHP-HEPT antagonism, and TCE-DEHP synergism were evident. Microphthalmia and anophthalmia incidences revealed TCE and DEHP main effects but no interactions. This extensive examination of a full-factorial design elucidates the complexities of studying and interpreting mixture toxicity. The data are available for further analysis.

Abnormalities, Drug-Induced↗
PubMed1995

Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer.

PURPOSE: Decisions concerning the use of hormone therapy to treat metastatic breast cancer are made on the basis of the presence of estrogen receptor (ER). Despite the presence of ER, half of patients will not respond to hormone treatment. The purpose of this study was to determine the effect of overexpression of HER-2/neu on the response to hormone therapy. PATIENTS AND METHODS: Sera from 300 metastatic breast cancer patients with ER-positive (ER+), ER status unknown, or ER-/progesterone receptor-positive (PR+) randomized to receive second-line hormone therapy with either megestrol acetate or fadrozole were evaluated. An enzyme immunoassay (EIA) specific for the extracellular domain of the c-erbB-2 (HER-2/neu) oncogene product was used to detect serum levels. RESULTS: Fifty-eight patients (19.3%) had elevated serum c-erbB-2 protein levels, using a selected cut-point of 30 U/mL. The response rate (complete responses [CRs] plus partial responses [PRs] plus stable disease [S]) to endocrine therapy was 40.9% in 242 patients with low serum c-erbB-2 levels and only 20.7% in 58 patients with elevated serum c-erbB-2 levels (P = .004). The median duration of treatment response was longer in the group with low serum c-erbB-2 levels (15.5 months) compared with the group with elevated serum c-erbB-2 levels (11.6 months). Survival was also significantly shorter in patients with elevated serum c-erbB-2 levels (P < .0001). CONCLUSION: Patients with ER+/c-erbB-2+ metastatic breast cancer are less likely to respond to hormone treatment than ER+/c-erbB-2- patients. Their survival duration is also shorter.

Adult↗
PubMed1995

The relationship between calcium, phosphorus, and sodium intake, race, and blood pressure in children with renal insufficiency: a report of the Growth Failure in Children with Renal Diseases (GFRD) Study.

Nutritional data compiled during the Growth Failure in Children with Renal Diseases Clinical Trial were analyzed to determine the relationship between the dietary intake of divalent minerals and sodium, nutritional status, and serum calcium, phosphorus, and parathyroid hormone (PTH) concentrations and blood pressure in black versus white children. One hundred eighteen patients are included in this report; 25 were black (21%) and 93 were white (79%). Although more of the blacks were male, the age distribution, midarm circumference, midarm muscle circumference, blood pressure, and serum calcium, phosphorus, and PTH concentrations were comparable in the two groups. Phosphorus intake was within the recommended daily allowance in both groups; in contrast, calcium intake was inadequate in all patients: 81% of the recommended daily allowance in whites, and 74% in blacks. Sixteen children were noted to be hypertensive during the observation period; six patients were receiving a variety of antihypertensive medications, including diuretics in two children. Linear regression analysis revealed that systolic and diastolic blood pressures were directly related to calcium and phosphorus intake in black patients. In white children, only dietary phosphorus intake and diastolic blood pressure were directly related. There was no relationship between sodium intake or GFR and blood pressure in the white or black children. PTH levels were directly correlated with systolic and diastolic blood pressure in all children. The correlations between PTH and blood pressure were stronger in white versus black patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Black People↗
PubMed1995

Biochemical markers of bone turnover in patients with metastatic bone disease.

Several biochemical markers of bone formation and bone resorption have recently been developed. These markers have been evaluated for clinical utility in patients with metabolic bone disease, including Paget disease and osteoporosis, and for their potential use in cancer patients whose disease has metastasized to bone. We have evaluated seven markers of bone turnover in the plasma and urine of 94 patients with newly diagnosed or progressive malignancy with and without clinical evidence of bone metastases. As determined by a positive bone scan and (or) bone survey, 30 patients had metastases to bone; 51 patients had metastatic cancer without overt bony involvement; and 13 patients had local disease without bone metastases. To evaluate the predictive value of these markers in the metastatic population, we utilized a "Z-score" and logistic regression analysis to distinguish patients with documented bone metastatic disease from those patients without clinical evidence of bone metastases. The higher the Z-score, the better the marker predicts the presence of bone metastases. With this statistical approach, urine N-telopeptide measurements had the highest Z-score and the most significant association with the probability of bone metastases. Urine deoxypyridinoline was the second most predictive marker of bone metastases. Thus, biochemical markers of bone resorption might be of use to predict the presence of bone metastases in cancer patients and to monitor the efficacy of antiresorptive therapy in patients treated for metastatic bone disease.

Alkaline Phosphatase↗
PubMed1995

Partial likelihood analysis of within-unit variances in repeated measurement experiments.

The objectives of some experiments are to compare the variances of two or more treatments, products, or techniques. If the investigator is more concerned about within-unit variances rather than between-unit variances, then a repeated measurement design is needed. We invoke a random effects model with heterogeneous within-unit variances for certain repeated measurement designs. We do not impose any distributional assumptions for the random effects, whereas we assume either a normal or multivariate t distribution for the random errors. We propose a partial likelihood analysis for population-based inference and individual-based inference. We illustrate the methodology with an example from a trial comparing serum cholesterol measurements from a routine laboratory analyzer to those of a standardized method.

Analysis of Variance↗
PubMed1995

Epidermal growth factor receptor ectodomain in the urine of patients with squamous cell carcinoma.

In this study we determined the levels of the epidermal growth factor receptor (EGFR) in the urine of patients with squamous cell carcinoma compared to levels in the urine of normal volunteers and patients with nonsquamous cell carcinoma. A 24-h urine specimen was collected from 50 normal volunteers, 50 patients with nonsquamous cell carcinoma, and 42 patients with squamous cell carcinoma. An ELISA using mAbs to the external domain of the EGFR was used to measure levels of the receptor in the urine samples. Measurement of the EGFR ectodomain in the 24-h urine specimens showed detectable levels in 15 (36%) of 42 squamous cell carcinoma patients compared to 3 (6%) of 50 controls and 8 (16%) of 50 nonsquamous patients. It was also observed that 10 (53%) of 19 patients with metastatic squamous cell carcinoma had detectable EGFR ectodomain levels compared to 5 (22%) of 23 squamous cell patients with localized disease. Thus, we concluded that the EGFR ectodomain was detectable in the urine in a significantly higher number of patients with squamous cell carcinoma than normal volunteers or patients with nonsquamous cell carcinoma.

3T3 Cells↗
PubMed1994

Bayesian hierarchical analysis of within-units variances in repeated measures experiments.

We develop hierarchical Bayesian models for biomedical data that consist of multiple measurements on each individual under each of several conditions. The focus is on investigating differences in within-subject variation between conditions. We present both population-level and individual-level comparisons. We extend the partial likelihood models of Chinchilli et al. with a unique Bayesian hierarchical framework for variance components and associated degrees of freedom. We use the Gibbs sampler to estimate posterior marginal distributions for the parameters of the Bayesian hierarchical models. The application involves a comparison of two cholesterol analysers each applied repeatedly to a sample of subjects. Both the partial likelihood and Bayesian approaches yield similar results, although confidence limits tend to be wider under the Bayesian models.

Algorithms↗
PubMed1994

A prospective, double-blind study of growth failure in children with chronic renal insufficiency and the effectiveness of treatment with calcitriol versus dihydrotachysterol. The Growth Failure in Children with Renal Diseases Investigators.

Because controlled trials in adults have shown accelerated deterioration of renal function in a small number of patients receiving calcitriol for renal osteodystrophy, we initiated a prospective, randomized, double-blind study of the use of calcitriol versus dihydrotachysterol in children with chronic renal insufficiency. We studied children aged 1 1/2 through 10 years, with a calculated glomerular filtration rate between 20 and 75 ml/min per 1.73 m2, and with elevated serum parathyroid hormone concentrations. Ninety-four patients completed a mean of 8.0 months of control observations and were randomly assigned to a treatment period; 82 completed the treatment period of at least 6 months while receiving a calcitriol dosage (mean +/- SD) of 17.1 +/- 5.9 ng/kg per day or a dihydrotachysterol dosage of 13.8 +/- 3.3 micrograms/kg per day. With treatment the height z scores for both calcitriol- and dihydrotachysterol-treated groups showed no differences between the two groups. In relation to cumulative dose, there was a significant decrease in glomerular filtration rate for both calcitriol and dihydrotachysterol; for calcitriol the rate of decline was significantly steeper (p = 0.0026). The treatment groups did not differ significantly with respect to the incidence of hypercalcemia (serum calcium concentration > 2.7 mmol/L (> 11 mg/dl)). We conclude that careful follow-up of renal function is mandatory during the use of either calcitriol or dihydrotachysterol because both agents were associated with significant declines in renal function. There was no significant difference between calcitriol and dihydrotachysterol in promoting linear growth or causing hypercalcemia in children with chronic renal insufficiency. Dihydrotachysterol, the less costly agent, can be used with equal efficacy.

Calcitriol↗
PubMed1994

Extension to the use of tolerance intervals for the assessment of individual bioequivalence.

For the determination of bioequivalence, researchers have recently shifted their emphasis from average bioequivalence alone to average and individual bioequivalence. Existing methods for assessing average bioequivalence were first developed for the standard 2 x 2 crossover design, but these methods are easily generalized to the two-treatment, p-period crossover designs (e.g., TRR, RTT, and TTRR, RRTT, TRRT, RTTR). With respect to individual bioequivalence, Westlake (1,2) implemented the use of parametric and distribution-free tolerance intervals for assessing individual bioequivalence. Anderson and Hauck (3) described what they call the test of individual equivalence ratios (TIER) for the same purpose. Note that these methods have been applied and/or developed only for the standard 2 x 2 crossover design. The present work extends the method of using parametric tolerance intervals for assessing individual bioequivalence.

Analysis of Variance↗
PubMed1994

Analysis of multiple-dose bioequivalence studies.

In multiple-dose bioequivalence studies, it is possible at steady state to take repeated measurements of pharmacokinetic variables, such as area under the curve (AUC) and the maximum concentration (CMAX) of the blood concentration-time profile, within each period of a crossover design. We develop a bivariate random effects model for such a situation in a 2 x 2 crossover design using the natural log scale for AUC and CMAX that assumes no differential carryover effects and includes components for inter- and intrasubject variability with respect to both formulations. We derive the uniformly minimum variance unbiased estimators, which also happen to be restricted maximum likelihood estimators, and we provide a sample size formula.

Cross-Over Studies↗
PubMed1994

Leukemia risk associated with benzene exposure in the pliofilm cohort: I. Mortality update and exposure distribution.

The National Institute of Occupational Safety and Health (NIOSH) recently completed a vital status update adding 6 years of observation on the rubber workers known as the Pliofilm cohort. Using traditional standardized mortality ratio (SMR) analysis, we investigate the impact of the additional information gathered in the NIOSH update. We also compare the effect of using three sets of job-, plant-, and year-specific exposure estimates on the evaluation of benzene's leukemogenicity. The lack of any additional cases of multiple myeloma does not support trends toward elevated risks for this endpoint (as had been observed earlier), and there is no indication of increased incidences of solid tumors (as predicted by animal studies). Qualitatively, which exposure estimates are used does not alter the conclusions. The data added in the update did not greatly modify the estimated relative risk of leukemia associated with benzene exposure, but did confirm previous findings that occupational exposure to high concentrations had leukemogenic potential. The fact that leukemia has not been observed in any individual who started employment in Pliofilm production after 1950 suggests that the observed leukemia cases could be a response to very high levels of benzene exposure that occurred during the early years of this manufacturing process.

Adult↗
PubMed1994

Leukemia risk associated with benzene exposure in the pliofilm cohort. II. Risk estimates.

The detailed work histories of the individual workers composing the Pliofilm cohort represent a unique resource for estimating the dose-response for leukemia that may follow occupational exposure to benzene. In this paper, we report the results of analyzing the updated Pliofilm cohort using the proportional hazards model, a more sophisticated technique that uses more of the available exposure data than the conditional logistic model used by Rinsky et al. The more rigorously defined exposure estimates derived by Paustenbach et al. are consistent with those of Crump and Allen in giving estimates of the slope of the leukemogenic dose-response that are not as steep as the slope resulting from the exposure estimates of Rinsky et al. We consider estimates of 0.3-0.5 additional leukemia deaths per thousand workers with 45 ppm-years of cumulative benzene exposure to be the best estimates currently available of leukemia risk from occupational exposure to benzene. These risks were estimated in the proportional hazards model when the exposure estimates of Crump and Allen or of Paustenbach et al. were used to derive a cumulative concentration-by-time metric.

Aged↗
PubMed1994

Maternal and fetal brain and plasma levels of cocaine and benzoylecgonine after acute or chronic maternal intravenous administration of cocaine.

The effect of repeated i.v. administration of cocaine HCl (1.5, 3 or 6 mg/kg daily) from gestational day 8 through gestational day 18 was studied on maternal and litter parameters in the pregnant female Sprague-Dawley rat. These doses of cocaine had no significant effect on maternal weight gain or nutritional intake and did not significantly affect litter size. Levels of cocaine and its metabolite benzoylecgonine in the brain and plasma of the dams and their fetuses were measured on gestational day 18 at 1, 5, 20 or 60 min after a single injection or 11 daily i.v. injections of cocaine (6 mg/kg). The shape of the time courses for cocaine differed somewhat between dams and fetuses, with fetal plasma concentrations of cocaine initially being lower than those of their dams and then by 5 min becoming equivalent to those of their dams. Although plasma concentrations of cocaine soon equilibrated between dams and fetuses, plasma concentrations of benzoylecgonine did not. Interestingly, brain concentrations of cocaine did not differ between dams and fetuses. The most remarkable finding was that the relative distribution of cocaine between brain and plasma differed after chronic vs. acute treatment, with a relative shift in the distribution of cocaine from plasma to the brain in the fetuses, and with the exception of the earliest time point measured, in the dams after repeated dosing.

Animals↗
PubMed1994

Evaluating test methods by estimating total error.

A common procedure for evaluating a test method by comparison with another, well-accepted method has been to use a repeated measurements design, in which several individual subjects' specimens are assayed with both methods. We propose the use of the intrasubject relative mean square error, which is a function of the intrasubject relative bias and the coefficient of variation of the test method, as a measure of total error. We construct for each individual subject a score that is based on how well an individual's estimate of total error compares with a maximum allowable value. If the individual's score is > 100%, then that individual's estimate of total error exceeds the maximum allowable value. We present a distribution-free statistical methodology for evaluating the sample of scores. This involves the construction of an upper tolerance limit to determine whether the test method yields values of the total error that are acceptable for most of the population with some level of confidence. Our definition of total error is very different from that defined in the National Cholesterol Education Program (NCEP) guidelines. The NCEP bound for total error has three main problems: (a) it incorrectly assumes that the standard error of the estimated relative bias is the test coefficient of variation; (b) it incorrectly assumes that the individual estimated relative biases follow gaussian distributions; (c) it is based on requiring the relative bias of the average individual in the population to lie within prescribed limits, whereas we believe it is more important to require the total error for most of the individuals in the population, say 95%, to lie within prescribed limits.

Bias↗
PubMed1994

Sample size considerations for assessing individual bioequivalence based on the method of tolerance intervals.

This is the consideration of sample sizes for assessing individual bioequivalence based on the use of tolerance intervals. The sample size procedures discussed include a direct distribution-free method, indirect parametric method and a direct parametric method. Design considerations are discussed based on the results of the direct parametric method. Tables are provided for easy access of results.

Biological Availability↗
PubMed1993

Masking of physicians in the Growth Failure in Children with Renal Diseases Clinical Trial.

Masking--hiding identities of treatments from the patient, physician and/or statistician--is a critical element in clinical trials. Wherever possible, masking is implemented to eliminate observational bias or systematic error. In this paper, general concepts of masking in clinical trials are examined. Specific masking procedures used in the "Growth Failure in Children with Renal Diseases" (GFRD) Clinical Trial are described. A method to evaluate the "success" of this masking procedure for physicians is introduced. For each randomized patient at each clinical center, the clinic director was asked to predict which treatment (1,25-dihydroxyvitamin D3 or dihydrotachysterol) was assigned. Results showed that 72% of responses initially indicated "absolutely no idea" of treatment. Additional analyses revealed that the number and percentage of "correct" guesses were essentially equal for the two treatment groups and that a patient's time on treatment did not affect the mask. We conclude that the mask of physicians in the GFRD Clinical Trial was well maintained.

Bias↗
PubMed1993

Total error assessment of five methods for cholesterol screening.

We report the accuracy, imprecision, total analytical errors, and patient misclassification errors for cholesterol measured from capillary whole blood, venous whole blood, and venous plasma samples by five devices used in public cholesterol screening environments: Reflotron, Vision, Ektachem DT-60, QuickRead, and Liposcan. None of the methods met the National Cholesterol Education Program (NCEP) performance recommendations of 3% CV with 3% bias. The Vision and Reflotron methods used with venous samples gave individual results with total errors consistent with a combined CV and bias in the 4-5% range; capillary blood samples had total errors > 5% (combined CV and bias criteria). The DT-60 performance was near the 5% total error criterion for capillary samples and was > 5% for venous samples. Misclassification of individuals into desirable or referral groups for venous samples was as great as 5.1% for the DT-60, 5.7% for the Vision, and 7.1% for the Reflotron. Misclassifications for capillary blood samples were as great as 6.7%, 18.3%, and 14.1% for DT-60, Vision, and Reflotron, respectively. The QuickRead and Liposcan results were substantially poorer than those obtained by the other methods.

Adult↗