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PubMed2000

Sample size in guidelines trials.

In clinical trials, the statistical concepts of significance and power are used in the determination of sample size for trials. The trialist must provide an estimate of standard deviation and a hypothetical population difference to be detected. This must be modified to deal with the designs encountered in guideline research. These are cluster randomized trials, because the patients of a single doctor or practice form a cluster. The trialist must be able to provide information about the effects of clustering, in the form of an intraclass correlation coefficient.

Family Practice↗
PubMed2002

Inbreeding depression: tests of the overdominance and partial dominance hypotheses.

The two principal theories of the causal mechanism for inbreeding depression are the partial dominance hypothesis and the overdominance hypothesis. According to the first hypothesis, inbreeding increases the frequency of homozygous combinations of deleterious recessive alleles thereby decreasing fitness, whereas the overdominance hypothesis posits that inbreeding increases homozygosity and thus reduces the frequency of the superior heterozygotes. These two hypotheses make different predictions on the effect of crossing inbred lines: the overdominance hypothesis predicts that trait means will be restored to the outbred means, whereas the partial dominance hypothesis predicts that trait means will exceed those of the outbred population. I tested these predictions using seven inbred lines of the sand cricket, Gryllus firmus. Fourteen generations of brother-sister mating resulted in an inbreeding depression of 20-34% in four traits: nymphal weights at ages 14 days, 21 days, 28 days, and early fecundity. An incomplete diallel cross of these lines showed genetic variation among lines and an increase in all trait means above the outbred means, with three being significantly higher. These results provide support for the partial dominance hypothesis and are inconsistent with the overdominance hypothesis.

Analysis of Variance↗
PubMed2002

Flexible matching strategies to increase power and efficiency to detect and estimate gene-environment interactions in case-control studies.

Lack of power is a pertinent problem in many case-control studies of gene-environment interactions. The authors recently introduced the concept of flexible matching strategies with varying proportions of a matching factor among selected controls (degree of matching) to increase the power and efficiency of case-control studies. In this study, they extended the concept of flexible matching strategies to the field of gene-environment interactions. They assessed the power and efficiency of such studies to detect and estimate gene-environment interactions under a variety of assumptions regarding the prevalence and effects of the environmental exposure and the genetic susceptibility as well as their association in the population. For each set of parameters, 10,000 case-control studies were simulated using varying degrees of matching. Traditional frequency matching increased the power and precision in most scenarios, but even greater gains were often obtained by increasing the prevalence of the environmental exposure in controls above the one in cases. The authors concluded that flexible matching strategies can increase the power and efficiency of case-control studies to detect and estimate gene-environment interactions compared with traditional frequency matching and therefore might help to alleviate the notorious lack of power of these studies in specific situations.

Case-Control Studies↗
PubMed1999

Assessment of the quality and quantity of drug-drug interaction studies in recent NDA submissions: study design and data analysis issues.

This report investigates the quality and quantity of drug-drug interaction studies in recent new drug applications (NDAs). Eighty-nine studies contained in 14 NDAs submitted between December 1995 and November 1996 to the U.S. Food and Drug Administration (FDA) were reviewed. The results indicated that the median number of clinical drug-drug interaction studies per NDA was 6, almost double that of a 1994-1995 survey. In vitro metabolism data were present in 70% of the submissions. More than 50% of the submissions contained interaction studies using a battery of drugs (cimetidine, digoxin, or warfarin) without optimal use of the in vitro metabolism or in vivo mass balance data. Various study designs using a median number of 12 subjects were employed in the evaluation of drug-drug interactions. Some of the important study design factors such as dose size, dosing regimen, dosing duration, and timing of coadministration were considered, although not consistently, by the sponsors in their study design. Seventy-five percent of the studies used normal, healthy male subjects, and 25% used patients for whom the new molecular entities were intended. In 33% of the studies, female subjects were also recruited. Although the majority (80%) of the submissions still used p-values to determine the significance of drug interactions, 30% used a more relevant equivalence approach with 90% confidence intervals for key pharmacokinetic and/or pharmacodynamic parameter ratios to assess the extent of drug interactions. Overall, 82% of the studies concluded no interaction. Although population pharmacokinetic analysis can be a useful tool in studying drug-drug interactions, only 21% of the submissions used this approach. In summary, this assessment reveals that the quantity and quality of drug-drug interaction studies in NDAs have improved over the years. These improvements, as well as others that can be implemented, should result in more informative labeling and better patient care. FDA guidance for industry dealing with the design, analysis, and labeling language of in vivo metabolic drug-drug interactions has been developed to assist sponsors and FDA reviewers with these issues.

Clinical Trials as Topic↗
PubMed2001

The inhaled Steroid Treatment as Regular Therapy in early asthma (START) study: rationale and design.

Although the beneficial effects of treatment with inhaled steroids in asthma are widely accepted, the role of early intervention in patients with mild asthma remains unsettled. Conventional efficacy trials are often of short duration and involve highly selected patient populations that exclude many patients typical of those encountered in routine clinical practice. Hence, a large "real-world" effectiveness study is needed to evaluate the benefits of early intervention with inhaled steroids in patients with mild, persistent asthma. In the START (inhaled Steroid Treatment As Regular Therapy in early asthma) study, patients ages 6-60 years, from 31 countries and districts worldwide with mild persistent asthma, have been randomized to once-daily treatment with budesonide, 200 microg (for patients < 11 years) or 400 microg (for patients > or = 11 years), or placebo via Turbuhaler for 3 years. The double-blind treatment period will be followed by a 2-year period of open budesonide treatment. Throughout the study, other asthma medication including glucocorticosteroids can be given as judged appropriate by the investigator. Lung function will be measured by spirometry using standardized techniques at 3-month intervals throughout the study, and bronchodilator reversibility will be measured annually. The primary outcome measures are the time to the first severe asthma-related event during the first 3 years of the study and the change in postbronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline during the entire 5-year study period. These measures have been chosen to reflect the progression of mild asthma toward more severe asthma and the extent of irreversible airflow limitation, which should reflect the degree of airway remodeling.

Acute Disease↗
PubMed1997

Statistical and study design issues in assessing the quality and outcomes of care in rheumatic diseases.

As we have pointed out in this article, a health care study should have a well-defined intent that is matched to the study type, population of interest, and outcome. Care must be taken to collect samples in a meaningful way, so that results can be generalized to larger populations. Outcomes must be selected carefully to ensure that they will be sensitive to the types of care being considered, and only a few main outcomes should be selected so as to preserve the level of statistical significance of the research results. Sample sizes should be sufficient to detect an effect of reasonable size, after accounting for attrition in longitudinal studies and rates of occurrence with dichotomous outcomes. If the study purpose is to compare multiple institutions or health care providers, statistical adjustments for case mix will generally be required. Outcome research is an expanding area of development for rheumatology care and for medical care in general. It offers the promise of the use of administrative data bases to answer questions that are important both to arthritis researchers and to consumers of rheumatology care. As with all areas of clinical research, we must maintain appropriate levels of statistical rigor to protect the integrity of the results. Inadequate attention to the design and analysis of data can compromise research results before a study even gets started, and health care research studies have as many potential statistical pitfalls as other types of clinical research.

Epidemiologic Studies↗
PubMed2000

Chemical precipitation of apolipoprotein B-containing lipoproteins facilitates determination of LDL particle size.

OBJECTIVES: To simplify the determination of low-density lipoprotein (LDL) particle size by eliminating the need for ultracentrifugation. DESIGN AND METHODS: We compared LDL particle size determination by gradient gel electrophoresis using two different methods for separation of LDL: (a) by ultracentrifugation with a density between 1.019 and 1.063 g/mL, and (b) by precipitation of the apolipoprotein B-containing lipoproteins from plasma. LDL particle size was determined for 41 individuals using both methods. RESULTS: The correlation between these two methods was r = 0.98; peak particle diameter (nm) was reproducible with a coefficient of variation of 1. 3% for LDL separated by ultracentrifugation and 1.4% for LDL prepared by precipitation. The intra-assay variation within a single gel was 0.2%. CONCLUSION: Elimination of the need for ultracentrifugation or lipid staining significantly reduces the cost and simplifies the procedure of LDL particle sizing. As a result, larger patient populations can be more readily screened for the determination of LDL particle size.

Adult↗
PubMed1996

How interchangeable are different estimators of effect size?

The computation of effect sizes is a key feature of meta-analysis. In treatment outcome meta-analyses, the standardized mean difference statistic on posttest scores (d) is usually the effect size statistic used. However, when primary studies do not report the statistics needed to compute d, many methods for estimating d from other data have been developed. Little is known about the accuracy of these estimates, yet meta-analysts frequently use them on the assumption that they are estimating the same population parameter as d. This study investigates that assumption empirically. On a sample of 140 psychosocial treatment or prevention studies from a variety of areas, the present study shows that these estimates yield results that are often not equivalent to d in either mean or variance. The frequent mixing of d and other estimates of d in past meta-analyses, therefore, may have led to biased effect size estimates and inaccurate significance tests.

Electronic Data Processing↗
PubMed1998

A discordant-sibship test for disequilibrium and linkage: no need for parental data.

The sibship disequilibrium test (SDT) is designed to detect both linkage in the presence of association and association in the presence of linkage (linkage disequilibrium). The test does not require parental data but requires discordant sibships with at least one affected and one unaffected sibling. The SDT has many desirable properties: it uses all the siblings in the sibship; it remains valid if there are misclassifications of the affectation status; it does not detect spurious associations due to population stratification; asymptotically it has a chi2 distribution under the null hypothesis; and exact P values can be easily computed for a biallelic marker. We show how to extend the SDT to markers with multiple alleles and how to combine families with parents and data from discordant sibships. We discuss the power of the test by presenting sample-size calculations involving a complex disease model, and we present formulas for the asymptotic relative efficiency (which is approximately the ratio of sample sizes) between SDT and the transmission/disequilibrium test (TDT) for special family structures. For sib pairs, we compare the SDT to a test proposed both by Curtis and, independently, by Spielman and Ewens. We show that, for discordant sib pairs, the SDT has good power for testing linkage disequilibrium relative both to Curtis's tests and to the TDT using trios comprising an affected sib and its parents. With additional sibs, we show that the SDT can be more powerful than the TDT for testing linkage disequilibrium, especially for disease prevalence >.3.

Alleles↗
PubMed2000

Removing the sampling restrictions from family-based tests of association for a quantitative-trait locus.

One strategy for localization of a quantitative-trait locus (QTL) is to test whether the distribution of a quantitative trait depends on the number of copies of a specific genetic-marker allele that an individual possesses. This approach tests for association between alleles at the marker and the QTL, and it assumes that association is a consequence of the marker being physically close to the QTL. However, problems can occur when data are not from a homogeneous population, since associations can arise irrespective of a genetic marker being in physical proximity to the QTL-that is, no information is gained regarding localization. Methods to address this problem have recently been proposed. These proposed methods use family data for indirect stratification of a population, thereby removing the effect of associations that are due to unknown population substructure. They are, however, restricted in terms of the number of children per family that can be used in the analysis. Here we introduce tests that can be used on family data with parent and child genotypes, with child genotypes only, or with a combination of these types of families, without size restrictions. Furthermore, equations that allow one to determine the sample size needed to achieve desired power are derived. By means of simulation, we demonstrate that the existing tests have an elevated false-positive rate when the size restrictions are not followed and that a good deal of information is lost as a result of adherence to the size restrictions. Finally, we introduce permutation procedures that are recommended for small samples but that can also be used for extensions of the tests to multiallelic markers and to the simultaneous use of more than one marker.

Alleles↗
PubMed2000

QTL fine mapping by measuring and testing for Hardy-Weinberg and linkage disequilibrium at a series of linked marker loci in extreme samples of populations.

It has recently been demonstrated that fine-scale mapping of a susceptibility locus for a complex disease can be accomplished on the basis of deviations from Hardy-Weinberg (HW) equilibrium at closely linked marker loci among affected individuals. We extend this theory to fine-scale localization of a quantitative-trait locus (QTL) from extreme individuals in populations, by means of HW and linkage-disequilibrium (LD) analyses. QTL mapping and/or linkage analyses can establish a large genomic region ( approximately 30 cM) that contains a QTL. The QTL can be fine mapped by examination of the degree of deviation from HW and LD at a series of closely linked marker loci. The tests can be performed for samples of individuals belonging to either high or low percentiles of the phenotype distribution or for combined samples of these extreme individuals. The statistical properties (the power and the size) of the tests of this fine-mapping approach are investigated and are compared extensively, under various genetic models and parameters for the QTL and marker loci. On the basis of the results, a two-stage procedure that uses extreme samples and different tests (for HW and LD) is suggested for QTL fine mapping. This two-step procedure is economic and powerful and can accurately narrow a genomic region containing a QTL from approximately 30-1 cM, a range that renders physical mapping feasible for identification of the QTL. In addition, the relationship between parameterizations of complex diseases, by means of penetrance, and those of complex quantitative traits, by means of genotypic values, is outlined. This means that many statistical genetic methods developed for searching for susceptibility loci of complex diseases can be directly adopted and/or extended to QTL mapping for quantitative traits.

Alleles↗
PubMed2000

A test for linkage and association in general pedigrees: the pedigree disequilibrium test.

Family-based tests of linkage disequilibrium typically are based on nuclear-family data including affected individuals and their parents or their unaffected siblings. A limitation of such tests is that they generally are not valid tests of association when data from related nuclear families from larger pedigrees are used. Standard methods require selection of a single nuclear family from any extended pedigrees when testing for linkage disequilibrium. Often data are available for larger pedigrees, and it would be desirable to have a valid test of linkage disequilibrium that can use all potentially informative data. In this study, we present the pedigree disequilibrium test (PDT) for analysis of linkage disequilibrium in general pedigrees. The PDT can use data from related nuclear families from extended pedigrees and is valid even when there is population substructure. Using computer simulations, we demonstrated validity of the test when the asymptotic distribution is used to assess the significance, and examined statistical power. Power simulations demonstrate that, when extended pedigree data are available, substantial gains in power can be attained by use of the PDT rather than existing methods that use only a subset of the data. Furthermore, the PDT remains more powerful even when there is misclassification of unaffected individuals. Our simulations suggest that there may be advantages to using the PDT even if the data consist of independent families without extended family information. Thus, the PDT provides a general test of linkage disequilibrium that can be widely applied to different data structures.

Alleles↗
PubMed1998

The significance of non-significance.

We discuss the implications of empirical results that are statistically non-significant. Figures illustrate the interrelations among effect size, sample sizes and their dispersion, and the power of the experiment. All calculations (detailed in Appendix) are based on actual noncentral t-distributions, with no simplifying mathematical or statistical assumptions, and the contribution of each tail is determined separately. We emphasize the importance of reporting, wherever possible, the a priori power of a study so that the reader can see what the chances were of rejecting a null hypothesis that was false. As a practical alternative, we propose that non-significant inference be qualified by an estimate of the sample size that would be required in a subsequent experiment in order to attain an acceptable level of power under the assumption that the observed effect size in the sample is the same as the true effect size in the population; appropriate plots are provided for a power of 0.8. We also point out that successive outcomes of independent experiments each of which may not be statistically significant on its own, can be easily combined to give an overall p value that often turns out to be significant. And finally, in the event that the p value is high and the power sufficient, a non-significant result may stand and be published as such.

Analysis of Variance↗
PubMed1999

Statistical power of MRI monitored trials in multiple sclerosis: new data and comparison with previous results.

OBJECTIVES: To evaluate the durations of the follow up and the reference population sizes needed to achieve optimal and stable statistical powers for two period cross over and parallel group design clinical trials in multiple sclerosis, when using the numbers of new enhancing lesions and the numbers of active scans as end point variables. METHODS: The statistical power was calculated by means of computer simulations performed using MRI data obtained from 65 untreated relapsing-remitting or secondary progressive patients who were scanned monthly for 9 months. The statistical power was calculated for follow up durations of 2, 3, 6, and 9 months and for sample sizes of 40-100 patients for parallel group and of 20-80 patients for two period cross over design studies. The stability of the estimated powers was evaluated by applying the same procedure on random subsets of the original data. RESULTS: When using the number of new enhancing lesions as the end point, the statistical power increased for all the simulated treatment effects with the duration of the follow up until 3 months for the parallel group design and until 6 months for the two period cross over design. Using the number of active scans as the end point, the statistical power steadily increased until 6 months for the parallel group design and until 9 months for the two period cross over design. The power estimates in the present sample and the comparisons of these results with those obtained by previous studies with smaller patient cohorts suggest that statistical power is significantly overestimated when the size of the reference data set decreases for parallel group design studies or the duration of the follow up decreases for two period cross over studies. CONCLUSIONS: These results should be used to determine the duration of the follow up and the sample size needed when planning MRI monitored clinical trials in multiple sclerosis.

Adolescent↗
PubMed2000

Examination of hemolytic potential with the On-X(R) prosthetic heart valve.

BACKGROUND AND AIM OF THE STUDY: Mechanical valves are known to produce chronic, subclinical hemolysis in most patients. Generally, haptoglobin is reduced to below normal in most patients, while lactate dehydrogenase (LDH) is increased to as much as 200% above the upper normal, sometimes resulting in anemia. The study was designed to investigate the clinical hemolysis of the On-X(R) prosthetic heart valve in a multicenter experience with a standard protocol and a single clinical laboratory. METHODS: Between September 1996 and August 1998, 248 patients underwent isolated valve replacement at 10 European centers. Blood samples were collected from these preoperatively and at 3-6 months and one year postoperatively. All samples were analyzed at a central laboratory, thus assuring poolability of the data. In total, 151 patients were tested at 3-6 months, and 62 at one year. Blood parameters measured were LDH, haptoglobin, hematocrit, total hemoglobin, red cell count and reticulocyte count. Paired analysis was used to compare preoperative baseline values with 3-6-month and one-year values. Data were analyzed with regard to both valve position and size. RESULTS: At 3-6 months and one year after surgery, average values for hematocrit, hemoglobin, red cell count and reticulocyte count were all near the center of the normal range, regardless of valve position or size. Statistically significant increases in red cell count and decreases in reticulocyte count occurred after both aortic valve replacement (AVR) and mitral valve replacement (MVR). These changes were of no clinical importance, but indicate that anemia has not occurred in these patients. At 3-6 months, haptoglobin was reduced to below normal in 86% of both AVR and MVR patients; this also occurred after one year and was statistically significant. Postoperatively, the mean LDH value in AVR was 228 U/l (91% of upper normal, 250 U/l) at 3-6 months, and 246 U/l (98% of upper normal) at one year. In MVR, these LDH values were 271 U/l (108% of upper normal) and 265 U/l (106% of upper normal). CONCLUSIONS: These results indicate that the On-X valve causes lower levels of chronic hemolysis in the immediate postoperative period and up to one year after surgery, especially when compared with reports of LDH elevations up to 200% of upper normal. Hemolytic anemia has not occurred in this patient population.

Aortic Valve↗
PubMed1992

[Detection of the safety depth on human chest by computer tomographic scanning].

Knowledges of acupuncture has played a major role in the treatment of human diseases, and has been mentioned in ancient Chinese medical literature for thousands of years. The loci which are most commonly used as treatment sites are points on the Ren Channel, kidney Channel, Stomach Channel, Pericardium Channel, Lung Channel, Spleen Channel and Gallbladder Channel for those loci on the human chest, insertion depth beyond safety level, can create serious consequences other such as pneumothorax, internal organ bleeding or other damage. This study was designed to determine the real safety depth for each locus by using a current scientific approach. The study was carried out at Tri-Service General Hospital and Mackay General Hospital. The sample patient population was 120. According to their body weight and height, patients were divided into six groups with various body sizes, i.e. normal, over and under-weight adults, and by sex differences. After computer tomographic scanning chest, the relative acupuncture loci should be measured according to anatomical position, then the distance between surface of the chest and thoracic pleura can be defined as its safety depth. For each locus of the groups, the mean and its interval of confident can be found. The analysis of variance (ANOVA), t-test, and multiple regression were also calculated by computer. The results show that there are significant differences in body chest loci within the same sex but, for different body sizes, statistically significant differences for each locus appear, so the safety depth for each chest locus has actually been proved. Not only does his data provide useful information for clinical practices, but also the standard safety depth for each loci on the chest could this be established.

Acupuncture Points↗