Clinical trial design in dermatology: experimental design. Part I.
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Adult↗
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The application of experimental design in bioengineering.
The use of factorial designs in experimentation and the careful planning of the three basic phases of experimental projects, will maximize the reliable information from the experiment and minimize the cost and effort to the experimentor. The application of the principles of good experimental design are illustrated in a case study of experimentation which investigates a new mode of peritoneal dialysis.
Biomedical Engineering↗
Experimental design deck for clinical research: A new learning resource in aid of scientific thinking.
The Experimental Design Deck for Clinical Research is a simulation of a problem in experimental design in a card deck format. It is intended to stimulate the development of skills in scientific thinking by allowing the student, in a self-directed fashion, to design a clinical trial to test either a given hypothesis (specific deck) or a hypothesis that the player provides (general deck). In addition to its use as an educational tool, the Experimental Design Deck can be used as a guide to the application of scientific thinking in a variety of biomedical activities. It can easily be modified for application to problems in nonmedical research and evaluation.
Clinical Trials as Topic↗
An unbalanced experimental design for dose response studies.
Sixty sets of real data for 15 different pesticides from both sexes of Balb/C mice in two different experimental designs were generated at NCTR. The quantal responses for the dose groups in this data ranged from 1% to 90%. It was shown that the data could be represented equally well by a probit or logit transformation. It was further shown that the investment in terms of 7 times as many animals would greatly increase the confidence in estimating the parameters of the model and in predicting the dose at the low end of the dose response. Most important, it was shown that the estimation of a safe dose for a specified risk was greatly influenced by the choice of experimental design and method of extrapolation. It might be worth the investment in better experimental design to both the consumer and to the chemical industry if higher safe doses could be established which would allow the chemical to better accomplish its purpose and yet improve the assurance of the safety of the consumer.
Animals↗
Oral nitroglycerin as a prophylactic antianginal drug: clinical, physiologic, and statistical evidence of efficacy based on a three-phase experimental design.
With the use of a three-phase experimental design, the efficacy of oral nitroglycerin has been evaluated in a total of 53 patients with documented angina pectoris due to coronary artery disease. The study were a double-blind, randomized, and cross-over comparison of controlled-release nitroglycerin (2.6 mg. tablets administered three times daily) and an indistinguishable placebo. Sixteen patients recorded anginal symptoms by the diary method over a 6 month trial of randomly sequenced 1 month periods of drug or placebo. In 15 patients, ST segments were monitored with a Holter dynamic electrocardiograph for periods of 10 to 12 hours under normal life style and evaluated by matching activities during periods of drug and placebo. In 22 patients, a multistage treadmill exercise test was conducted to an endpoint of anginal pain. The three phases of the investigation were run in succession; each phase was completed before the next one was begun. Oral nitroglycerin reduced the incidence and severity of anginal attacks by 47.2 and 49.4 per cent, respectively, and decreased the number of sublingual nitroglycerin tablets used by 51.1 per cent in comparison to placebo (p less than 0.001). Eleven of 16 patients (69 per cent) decreased their need for sublingual nitroglycerin by over 50 per cent. Based on a polynomial trend analysis over a period of 8 weeks, no tolerance to the therapeutic effects of the drug was found. With DCG monitoring, drug decreased the ST segment depression from 1.76 mm. on placebo to 1.12 mm, with a significant difference of 0.64 mm. (p less than 0.001). ST segment depression was decreased more than 0.5 mm. by drug in comparison to placebo in 10 of 15 patients (66 per cent). Larger depressions of the ST segment noted with placebo at heart rates greater than 80 beats per minute were prevented by administration of the drug. During treadmill exercise, drug delayed the onset of pain by 83 seconds (64 per cent) over placebo (p less than 0.001) and decreased the duration of pain by 70 seconds (49 per cent) in comparison to placebo (p less than 0.001). Drug did not affect heart rate or systolic blood pressure at rest or after exercise, as well as rate-pressure product for production of angina following exercise (p less than 0.05). There was no side effects reported caused by the drug. The data demonstrate that oral nitroglycerin, given as controlled-release tablets, was absorbed from the gastrointestinal tract in quantities sufficient to provide statistically significant clinical improvement of angina pectoris.
Activities of Daily Living↗
Comparison and evaluation of some experimental designs for use in carcinogen screening.
The development and evaluation of experimental designs for routine in vivo screening of chemicals for potential carcinogenic activity were considered. Such designs have played an important role in the Carcinogenesis Bloassay Program of the National Cancer Institute (NCI). In particular, the current one-stage 50-animal/group screen used by the NCI was considered. A specific two-stage alternative was proposed in which 35 animals/group were used; this alternative allowed for retesting of equivocal compounds. The proposed designs were evaluated in terms of sensitivity, specificity, and throughout. Despite the large number of tests made for each compound, the false-positive rate was found to be less than 0.07 for the current screen and less than 0.05 for the proposed two-stage alternative. The power of the one-stage and two-stage screens was comparable. The two-stage screen was shown to make about 30% more decisions per test period with a savings of around 28% in the expected number of animals needed per compound tested.
Animals↗
Rationale and experimental design for the VA Cooperative Study of Anticoagulation (Warfarin) in the Treatment of Cancer.
Anticoagulants have been demonstrated to reduce tumor growth in certain experimental animal systems. Inhibition of clot formation interferes with tumor growth and spread while enhancement of coagulation promotes tumor growth and spread. The fact that the coagulation mechanism is commonly activated in human malignancy together with preliminary reports of therapeutic efficacy of anticoagulants suggests that the coagulation mechanism may be of pathophysiologic significance also in the growth of human tumors. A VA Cooperative Study has been established to test the hypothesis that warfarin anticoagulation will modify the course of malignancy in man. The purpose of this paper is to present the rationale and experimental design for this study with emphasis on management of anticoagulant administration in cancer patients. This paper serves as the basis for forthcoming reports of toxicity and therapeutic efficacy of warfarin in human malignancy.
Animals↗
Evaluation of the chronic inhalation toxicity of a manganese oxide aerosol--I. Introduction, experimental design, and aerosol generation methods.
A brief literature review on manganese toxicity is presented; as related to designing a chronic inhalation study for evaluating methylcyclopentadienyl manganese tricarbonyl when utilized as a motor fuel additive. The experimental design of this study is described. The generation system utilized to simulate the manganese aerosol produced by an internal combustion engine is described in detail. This generation system operated twenty-four hours per day, seven days per week producing aerosols at 11.6, 112.5, and 1152 micrograms Mn/m3 with an aerodynamic diameter of approximately 0.11 micron.
Aerosols↗
Experimental design and statistical analysis of an in-use test of germicidal detergents.
Present methodology for the in-use testing of germicidal detergents is too time-consuming for routine use by a hospital environmentalist. A simplified experimental design and statistical analysis, amenable to routine use, is presented for the in-use testing of germicidal detergents against water alone. As an illustration of our methodology we evaluated two germicidal detergents versus water alone. Under our conditions of use, it was found that water alone was equally and significantly as effective (p less than 0.001) as the two germicidal detergents in reducing microbial contamination of floors.
Anti-Infective Agents, Local↗
Apomorphine-induced locomotion and gnawing: evidence that the experimental design greatly influences gnawing while locomotion remains unchanged.
In a recent study we have shown that it was possible to recognize and record two independent behavioural patterns elicited by apomorphine (s.c.): one behaviour characterized by increased locomotion, sniffing and repetitive head and limb movements and another, characterized by compulsive gnawing. In the present study we have further characterized the gnawing and the locomotion patterns, their dependence on the experimental design and on the test environment. We found that the apomorphine-induced gnawing was easily modified by factors such as the design of the test-box and the habituation of the animal to the test-box. Locomotion, on the other hand was essentially independent of such factors and seemed more compulsive than the so-called "compulsive gnawing".
Animals↗
Dominant lethal assays in male mice: evaluation of experimental design, statistical methods and the sensitivity of Charles River (CD1) mice.
Male CD1 mice were dosed by intraperitoneal injection of 20, 40 or 80 mg of methyl methanesulphonate (MMS) per kg body weight or with the solvent, water. After dosing, each male was caged with (a) 2 or (b) 3 females per week for 8 consecutive weeks and 13 days after mating the females were killed and examined for evidence of dominant lethal mutations. Results were analysed to determine (1) the sensitivity of CD1 mice to the mutagenic effect of MMS. (2) the influence of the number of females mated with each male. (3) the adequacy of the experimental design and (4) the adequacy of the statistical methods. A dose-related increase in early foetal deaths was induced in females mated to male mice in the first week after dosing with 20, 40 and 80 mg/kg MMS. A reduction in foetal implants was demonstrated in females in the 40 and 80 mg/kg MMS groups but not after dosing males with 20 mg/kg. Thus dominant lethal mutations were induced in male CD1 mice dosed IP with 20, 40 and 80 mg/kg giving a degree of sensitivity which compares favourably with that obtained with other strains of mice in other laboratories. For a given number of male mice, the greater precision obtained with 3 rather than 2 females arose directly from the numbers used. For a given number of female mice, the allocation of 2 per male (rather than 3 per male) is a more efficient design in that 50% more treated animals are available for estimation of the relevant error. Also more information would be available as a result of the probable increase in pregnancy rate. The experiment did not suggest the need for any modification in the statistical approach.
Animals↗
A computer program for experimental design simulation.
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Computers↗
Factorial experimental design applied to the immunological study of two foot-and-mouth disease virus subtypes. 2. Theoretical study of experimental models.
A certain number of theoretical models of immunological relations that 2 foot-and-mouth disease viruses can support, were constructed so as to discuss in each case, the results of the factorial analysis of the data. This method provided a specific answer to each of the questions that were asked in the presence of a test of this kind. The results obtained with several immunological cross-tests comparable to that of the A Greece 69-A Allier viruses, illustrated most of the theoretical models.
Animals↗
Interaction of visual evoked potentials in groups of stimuli with different interstimulus intervals in cats. I. Experimental design. Dispersion analysis.
Quantitative estimation of excitability is performed at present in a pair of stimuli by studying the so-called recovery cycles. Random mixing of the interstimulus intervals and their appropriate grouping (grouped pairs) can provide new information about the course of excitability in time. An experimental setup is described in which by planning of the experiment (BIB-design) the interstimulus intervals are randomized and all components of the evoked potentials (EP) are placed under equal conditions with respect to the influence of the preceding intervals. The effects of the interstimulus intervals simultaneously on different components of visual evoked potentials in cats are estimated by means of dispersion analysis. The results show the existence of a significant effect only on definite amplitudes of the EP (predominantly with great latencies). The interactions of the effects of definite interstimulus intervals are determined, which permits the assumption of an interaction among different components of EP.
Animals↗
Experimental design for the surgical relocation of the ovary into the vaginal fornix.
After translocation into the vaginal vault while attached to a pedicle consisting of the infundibulo-pelvic ligament, the ovary was found to maintain its function in laboratory primates. In the majority of the baboons the ovulatory pattern returned within a few weeks after the surgical procedure. The only significant complication was a transitory, and self-limited, infection which was evident on inspection and on the biopsy specimens, but caused no clinical symptoms. By comparing the surgical outcome in two primate species, namely Papio Cynocephalus and Macaca Arctoides, it could be deduced that the Homo Sapiens would be a more suitable experimental model than either of the laboratory primates used in this research. Because there are potentially effective methods for reducing the likelihood of postoperative infection in the relocated ovary, the experience gained by this new method suggests the possibility that it could be utilized in the future for the purpose of collecting ova for in vitro fertilization in carefully selected, and otherwise untreatable, cases of female sterility.
Animals↗
Operative staging of apparently localized adenocarcinoma of the prostate: results in fifty unselected patients. I. Experimental design and preliminary results.
The design and details of a prospective, randomized study protocol involving bipedal lymphography, and exploratory laparotomy with selective node biopsy in patients with apparently localized adenocarcinoma of the prostate are presented. The analysis includes the results of selected diagnostic tests, and an assessment of the accuracy of clinical vs. surgical staging in 50 unselected patients. Lymphatic metastases were found at the time of diagnostic laparotomy in 18 of the 50 patients (36%). Both increasing size (advanced T stage) and decreasing differentiation of the primary tumor were associated with an increased incidence of lymph node metastases. Of 25 patients with T1 and T2 tumors (Stage B), and 25 patients with T3 tumors (Stage C), lymphatic dissemination was found in 20 and 52%, respectively. Eleven of 20 patients (55%) with poorly differentiated tumors had lymph node metastasis, compared with only 2 or 11 patients (18%) with well-differentiated tumors. Twelve patients had a change in their clinical stage following exploratory laparotomy; in eight the stage was increased and in four it was decreased. Of 18 patients with lymphatic metastases, some of which were extensive and most of which were associated with increased serum acid phosphatase values, no evidence of concurrent bony or visceral dissemination was found. Although preliminary, this finding should stimulate the search for effective treatment in these patients who were previously thought to be incurable on the basis of probable vascular dissemination.
Acid Phosphatase↗
Anatomical substages of stage III Hodgkin's disease: implications for staging, therapy, and experimental design.
Twenty-three patients with pathologic stage III Hodgkin's disease were classified with respect to the presence or absence of symptoms (III-A, III-B), the presence or absence of splenic involvement (IIIS+, IIIS-) and anatomic substage--the extent of disease within the abdomen (III1, III2). Stage III1 disease included disease limited to the upper abdomen, i.e., spleen, splenic node, celiac node, and/or portal node. All other more extensive disease was classified as stage III2. Symptoms and splenic involvement did not predict either disease-free survival or survival. However, 5 year actuarial disease-free survival was significantly better in III1 patients as compared to III2 patients (77% vs. 13%, p less than .001). Eight of nine stage III2 patients receiving total nodal radiotherapy alone relapsed. When considered along the previous studies of anatomic substage, these findings suggest that patients in stage III1 and III2 should receive different therapeutic approaches. Analysis of therapeutic results in stage III patients must consider anatomic substage.
Abdomen↗
Drug concentrations in neuropsychiatry. Methodological pitfalls: the influence of experimental design on results.
The valid study of relationships between pharmacokinetic measurements and clinical effects of psychotropic drugs depends on: (i) analytical methods for the drugs; (ii) the fluid assessed and pharmacokinetic derivations; (iii) clinical assessments and the nature of psychiatric illness; and (iv) statistical work. Standard problems with analytical methods include lack of specificity, unjustified claims for sensitivity, and failure to recognize metabolites as potential analytical contaminants and compounds for separate study. Problems with pharmacokinetic derivations include inappropriate calculations and incorrect assignment of terms such as 'half-life'. Clinical difficulties mostly relate to variations between patient groups, selection procedures and rating methods, and to timing of samples. Statistical controversies concern the calculation of metabolite ratios, pooling of data from drugs and their metabolites, and abuse of statistical techniques. These methodological problems are illustrated by reference to work with phenothiazines, tricyclic antidepressants, lithium, benzodiazepines and anticonvulsants.
Body Fluids↗