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ABSTRACT: During the design and planning phase of clinical trials, researchers often assume that no covariate by treatment interaction exists. This assumption has led to many trials being underpowered to detect such interactions and perhaps inaccurate interpretation of treatment effects. We propose a two-stage adaptive design that incorporates the likely existence of a treatment by covariate interaction into the design and implementation of the clinical trial. The information in stage 1 is used to test for the presence of the covariate by treatment interaction. A statistically significant interaction influences how the second stage of the trial will be implemented, thereby aiding in the full understanding and consequently, an accurate interpretation of the treatment effect. We examine the statistical properties of the proposed design using a binary outcome under different types of covariate by treatment interactions and treatment allocation schemes. A conditional power approach is used to prevent inflation of the overall trial type I error rate while maintaining adequate statistical power conditional on the statistically significant interaction.
Contemporary clinical trials 06/2008; 29(3):428-38. · 1.51 Impact Factor
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ABSTRACT: Phase II trials often test the null hypothesis H(0): p <or= p(0) versus H(1): p >or=p(1), where p is the true unknown proportion responding to the new treatment, p(0) is the greatest response proportion which is deemed clinically ineffective, and p(1) is the smallest response proportion which is deemed clinically effective. In order to expose the fewest number of patients to an ineffective therapy, phase II clinical trials should terminate early when the trial fails to produce sufficient evidence of therapeutic activity (i.e. if p <or=p(0)). Simultaneously, if a treatment is highly effective (i.e. if p>or=p(1)), the trial should declare the drug effective in the fewest patients possible to allow for advancement to a phase III comparative trial. Several statistical designs, including Simon's minimax and optimal designs, have been developed that meet these requirements. In this paper, we propose three alternative designs that rely upon stochastic curtailment based on conditional power. We compare and contrast the properties of the three approaches: (1) stochastically curtailed (SC) binomial tests, (2) stochastically curtailed (SC) Simon's optimal design, and (3) SC Simon's minimax design to those of Simon's minimax and Simon's optimal designs. For each of these designs we compare and contrast the number of opportunities for study termination, the expected sample size of the trial under the null hypothesis (p <or=p(0)), and the effective type I and type II errors. We also present graphical tools for monitoring phase II clinical trials with stochastic curtailment using conditional power.
Statistics in Medicine 04/2007; 26(7):1462-72. · 1.88 Impact Factor
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S W Keith, D T Redden,
P T Katzmarzyk,
M M Boggiano,
E C Hanlon,
R M Benca,
D Ruden,
A Pietrobelli,
J L Barger,
K R Fontaine,
C Wang,
L J Aronne,
S M Wright,
M Baskin,
N V Dhurandhar,
M C Lijoi,
C M Grilo,
M DeLuca,
A O Westfall,
D B Allison
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ABSTRACT: To investigate plausible contributors to the obesity epidemic beyond the two most commonly suggested factors, reduced physical activity and food marketing practices.
A narrative review of data and published materials that provide evidence of the role of additional putative factors in contributing to the increasing prevalence of obesity.
Information was drawn from ecological and epidemiological studies of humans, animal studies and studies addressing physiological mechanisms, when available.
For at least 10 putative additional explanations for the increased prevalence of obesity over the recent decades, we found supportive (although not conclusive) evidence that in many cases is as compelling as the evidence for more commonly discussed putative explanations.
Undue attention has been devoted to reduced physical activity and food marketing practices as postulated causes for increases in the prevalence of obesity, leading to neglect of other plausible mechanisms and well-intentioned, but potentially ill-founded proposals for reducing obesity rates.
International Journal of Obesity 12/2006; 30(11):1585-94. · 4.69 Impact Factor
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Obesity Reviews 03/2004; 5(1):1-2. · 7.04 Impact Factor
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Journal of Pediatrics. 01/2004; 145:427 - 430.
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ABSTRACT: Most hemodialysis patients in the United States have an arteriovenous graft as their vascular access. Grafts have a relatively short life span and are prone to recurrent stenosis and thrombosis, requiring multiple salvage procedures to maintain their patency. There is little information in the literature regarding the clinical factors that determine graft survival and complications. We evaluated prospectively the outcomes of 256 grafts placed at a single institution during a 2-year period. A salvage procedure to maintain graft patency (thrombectomy, angioplasty, or surgical revision) was required in 29% of the grafts at 3 months, 52% at 6 months, 77% at 12 months, and 96% at 24 months. Thus, primary graft survival (time from graft placement to the first intervention) was only 23% at 1 year and 4% at 2 years. Primary graft survival was significantly less among patients with hypoalbuminemia compared with patients with a normal serum albumin level (P = 0.003). Secondary graft survival (time from graft placement to permanent graft failure) was 65% at 1 year and 51% at 2 years. Neither primary nor secondary graft survival was significantly correlated with patient age, sex, diabetic status, body mass index, or graft site. A mean of 1.22 interventions per graft-year were required to maintain access patency, including 0.51 thrombectomies, 0.54 angioplasties, and 0.17 surgical revisions. In conclusion, hypoalbuminemia is a strong predictor of the requirement for an early graft intervention. Patients with hypoalbuminemia may require a heightened index of suspicion in monitoring their grafts for evidence of stenosis.
American Journal of Kidney Diseases 08/2000; 36(1):68-74. · 5.43 Impact Factor
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ABSTRACT: The prevalence of obesity is higher in black than in white women. Differences in energy economy and physical activity may contribute to this difference.
The objective of this study was to compare free-living energy expenditure and physical activity in black and white women before and after weight loss.
Participants were 18 white and 14 black women with body mass indexes (in kg/m(2)) between 27 and 30. Diet, without exercise, was used to achieve a weight loss of >/=10 kg and a body mass index <25. After 4 wk of energy balance in overweight and normal-weight states, body composition was assessed by using a 4-compartment model, sleeping and resting energy expenditures were assessed by using a chamber calorimeter, physiologic stress of exercise and exercise economy were measured by using standardized exercise tasks, and daily energy expenditure was assessed by using doubly labeled water.
Weight loss averaged 12.8 kg. Sleeping and resting energy expenditures decreased in proportion to changes in body composition. Weight reduction significantly improved physiologic capacity for exercise in both groups of women, making it easier for them to be physically active. Black women had lower body composition-adjusted energy requirements than did white women-both before and after weight loss-during sleep (9% lower, 519 kJ/d; P < 0.001), at rest (14% lower, 879 kJ/d; P < 0.001), during exercise (6% lower; P < 0. 05), and as a daily total (9% lower, 862 kJ/d; P < 0.06). By contrast, free-living physical activity was similar between the groups.
Weight-reduced women had metabolic rates appropriate for their body sizes. Black women had lower resting and nonresting energy requirements in both overweight and normal-weight states than did white women and did not compensate with greater physical activity, potentially predisposing them to greater weight regain.
American Journal of Clinical Nutrition 05/2000; 71(5):1138-46. · 6.67 Impact Factor
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S Ren,
M J Smith,
I D Louro,
P McKie-Bell,
M R Bani,
M Wagner,
B Zochodne, D T Redden,
W E Grizzle,
N d Wang,
D I Smith,
R A Herbst,
W Bardenheuer,
B Opalka,
J Schütte,
J M Trent,
Y Ben-David,
J M Ruppert
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ABSTRACT: Gene amplification is frequently present in human tumors, although specific target genes relevant to many amplified loci remain unidentified. An expression cloning assay enabled identification of a candidate oncogene derived from human chromosome 3p14.1. The cDNA retrieved from morphologically transformed cells contained the full-length protein coding region and detected an abundant transcript in the same cells. Sequence analysis revealed identity with the wild-type sequence of p44S10, a highly conserved subunit of the 26S proteasome that exhibits similarity to the Arabidopsis fus6/cop11 family of signaling molecules. p44S10 gene copy number and mRNA expression were increased in association with segmental 1.8 - 11-fold chromosomal gains in cutaneous malignant melanoma cell lines (5/13; 40%) and tumors (2/40; 5%), and in breast cancer MCF-7 cells. Likewise, malignant progression of human radial growth phase WM35 melanoma cells was associated with amplification and increased expression of endogenous p44S10, and increased expression of p44S10 was sufficient to induce proliferation of WM35 cells in vivo. The results demonstrate segmental copy number gains within chromosome 3p in cutaneous malignant melanoma and suggest that deregulation of a proteasome regulatory particle subunit may contribute to the malignant phenotype.
Oncogene 04/2000; 19(11):1419-27. · 6.37 Impact Factor
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ABSTRACT: Dialysis access procedures and complications represent a major cause of morbidity, hospitalization, and cost for chronic dialysis patients. To improve the outcomes of hemodialysis access procedures, recent clinical guidelines have encouraged attempts to place an arteriovenous (A-V) fistula, rather than an A-V graft, whenever possible in hemodialysis patients. There is little information, however, about the success rate of following such an aggressive strategy in the prevalent dialysis population.
We evaluated the adequacy of all A-V fistulas placed in University of Alabama at Birmingham dialysis patients during a two-year period. A fistula was considered adequate if it supported a blood flow of >/=350 ml/min on at least six dialysis sessions in one month. Fistula adequacy was correlated with clinical and demographic factors.
The adequacy could be determined for 101 fistulas; only 47 fistulas (46.5%) developed sufficiently to be used for dialysis. The adequacy rate was lower in older (age >/= 65) versus younger (age < 65) patients (30.0 vs. 53.5%, P = 0.03). It was also marginally lower in diabetics versus nondiabetics (35.0 vs. 54.1%, P = 0.061) and in overweight (BMI >/= 27 kg/m2) versus nonoverweight patients (34.5 vs. 55.2%, P = 0.07). The adequacy rate was not affected by patient race, smoking status, surgeon, serum albumin, or serum parathyroid hormone. The adequacy rate was substantially lower for forearm versus upper arm fistulas (34.0 vs. 58.9%, P = 0.012). The adequacy of forearm fistulas was particularly poor in women (7%), patients age 65 or older (12%), and diabetics (21%). In contrast, upper arm fistulas were adequate in 56% of women, 54% of older patients, and 48% of diabetics.
An aggressive approach to the placement of fistulas in dialysis patients results in a less than 50% early adequacy rate, which is considerably lower than that reported in the past. Moreover, the success rate of fistulas is even lower for certain patient subsets. To achieve an optimal outcome with A-V fistulas, we recommend that they be constructed preferentially in the upper arm in female, diabetic, and older hemodialysis patients.
Kidney International 07/1999; 56(1):275-80. · 6.61 Impact Factor
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ABSTRACT: Recent efforts to improve survival outcome in patients with locally advanced non-small cell lung cancer have focused on the use of chemoradiotherapy regimens containing vinblastine/cisplatin or etoposide/cisplatin. However, the overall treatment outcome with these regimens remains poor, emphasizing the need for new therapeutic options. Based on the activity of paclitaxel in advanced non-small cell lung cancer, its additive cytotoxicity with cisplatin, and the radiation-sensitizing effect of both agents, a phase I/IIa study was designed to examine the feasibility of paclitaxel/cisplatin concurrently with conventional thoracic irradiation in patients with locally advanced tumors. One major concern regarding combined modality therapy has been the enhancement of pulmonary toxicity. This report describes the incidence and severity of pulmonary toxicities observed in this trial according to the Radiation Therapy Oncology Group scoring criteria. A literature-based review was performed in an attempt to determine the impact of paclitaxel-based versus non-paclitaxel-based chemoradiotherapy regimens on the early and late pulmonary morbidity. Twenty-four evaluable patients died and 14 (37%) are still alive without evidence of disease. The 1- and 2-year survival rates are 62% and 40%, respectively, with a median survival of 17 months. Pulmonary toxicity >/=grade 2 was more frequently manifested as late toxicity in approximately 70% of the patients. In most, prompt symptomatic and radiologic improvement was observed with the early administration of corticosteroids. There were three late grade 5 toxicities characterized by diffuse (bilateral) rapidly progressive interstitial infiltrates. Protracted lymphocytopenia was noted in the great majority of patients, and its role in the pathogenesis of this complication remains to be determined. There were minor changes in pulmonary function parameters, except in the forced vital capacity and diffusion capacity to carbon monoxide. In a univariate analysis, no relationship was noted between paclitaxel dose level, degree of lymphocytopenia, changes in pulmonary function indices, and incidence of pulmonary toxicity. However, there was a significant dose-volume relationship (using conventional dose-volume histograms) with late pulmonary toxicity at radiation doses between 15 Gy and 30 Gy. Based on a literature review, paclitaxel-based chemotherapy regimens seem to be associated with a slightly higher risk of pulmonary toxicity; however, comparison of such toxicity between trials has many limitations that require that the conclusion reached be viewed with caution.
Seminars in Radiation Onchology 05/1999; 9(2 Suppl 1):136-47. · 4.03 Impact Factor
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ABSTRACT: The purpose of this study was to demonstrate that a simple submaximal "step-test" could be used as an exercise challenge to identify elementary school students with suspected but undiagnosed asthma. This article also describes a protocol for exercise testing that can be used in epidemiological evaluations. School age children grades 1-4 with suspected but undiagnosed asthma were identified by a 12-item questionnaire completed by a parent or guardian. Only students identified with suspected asthma by questionnaire were exercise challenged on a step-test it baseline spirometry was normal and there was no contraindication for intense aerobic activity. Possible asthma was defined as a 15% or greater decrease in FEV1 or a 25% or greater decrease in FEF25-75 from baseline at either 3 or 10 minutes. The exercise protocol included spirometry before and after stepping continuously for 5 minutes at an exercise intensity sufficient to maintain a heart rate between 150 and 200 beats per minute. Heart rate was continuously monitored throughout the exercise period. Testing was completed at school. No complications occurred during the exercise testing. Exercise testing was completed on 548 students with suspected undiagnosed asthma. Thirty students (6%) had exercise test changes in pulmonary function that met established criteria for suspecting asthma. A board-certified pediatric allergist/immunologist or private physician examined 26 of the 30 students with positive exercise testing. Asthma was diagnosed in 23 (88.89%) of these students. All students with impaired pulmonary function after exercise were able to return to class after a short period of observation. In conclusion, a simple, reproducible school-based exercise protocol can be used to identify students with suspected undiagnosed asthma.
Allergy and Asthma Proceedings 20(3):181-8. · 2.17 Impact Factor
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ABSTRACT: It has been proposed that enteral feeding formulas containing small peptides are more efficacious and better tolerated than whole-protein formulas in critically ill patients.
Intensive care unit patients were stratified with regard to treatment with antibiotics and serum albumin and randomized to treatment with a small-peptide enteral diet or an isoenergetic, isonitrogenous whole-protein diet for 10 days. To assess efficacy, we measured serum prealbumin and fibronectin, and to assess tolerance, we monitored the incidence of diarrhea. A protocol was followed to ascertain all causes of diarrhea (defined as > 200 g stool or > or = 3 liquid stools on 2 consecutive days).
Fifty subjects completed the trial. Serum prealbumin and fibronectin increased between 21% and 36% in both groups, but the increase was significant only in the small-peptide group. The change in fibronectin between days 5 and 10 was significantly greater in the small-peptide group (p = .02). Diarrhea occurred in 10 subjects (17.8% of days) receiving small-peptide feeding and 4 subjects (7.5% of days) receiving whole-protein feeding (P = .07 for incidence and 0.03 for prevalence), but the difference was explained by the coincidental use of more diarrhea-causing medications in the former. Only one case of diarrhea could be attributed to tube feeding.
During 10 days of feeding, the small-peptide diet produced slightly greater increases in serum rapid-synthesis proteins than did the whole-protein diet, especially between days 5 and 10. The clinical implications of this difference between the diets are unknown. Both small-peptide and whole-protein diets were well tolerated.
Journal of Parenteral and Enteral Nutrition 21(3):162-7. · 3.29 Impact Factor
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ABSTRACT: During the design and planning phase of clinical trials, researchers often assume that no covariate by treatment interaction exists. This assumption has led to many trials being underpowered to detect such interactions and perhaps inaccurate interpretation of treatment effects. We propose a two-stage adaptive design that incorporates the likely existence of a treatment by covariate interaction into the design and implementation of the clinical trial. The information in stage 1 is used to test for the presence of the covariate by treatment interaction. A statistically significant interaction influences how the second stage of the trial will be implemented, thereby aiding in the full understanding and consequently, an accurate interpretation of the treatment effect. We examine the statistical properties of the proposed design using a binary outcome under different types of covariate by treatment interactions and treatment allocation schemes. A conditional power approach is used to prevent inflation of the overall trial type I error rate while maintaining adequate statistical power conditional on the statistically significant interaction.
Contemporary Clinical Trials.
