Transmission/disequilibrium tests using multiple tightly linked markers.
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Transmission/disequilibrium tests have attracted much attention in genetic studies of complex traits because (a) their power to detect genes having small to moderate effects may be greater than that of other linkage methods and (b) they are robust against population stratification. Highly polymorphic markers have become available throughout the human genome, and many such markers can be studied within short physical distances. Studies using multiple tightly linked markers are more informative than those using single markers. However, such information has not been fully utilized by existing statistical methods, resulting in possibly substantial loss of information in the identification of genes underlying complex traits. In this article, we propose novel statistical methods to analyze multiple tightly linked markers. Simulation studies comparing our methods versus existing methods suggest that our methods are more powerful. Finally, we apply the proposed methods to study genetic linkage between the dopamine D2 receptor locus and alcoholism. (+info)
Sample sizes for cancer trials where Health Related Quality of Life is the primary outcome.
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Health Related Quality of Life (HRQoL) instruments are increasingly important in evaluating health care, especially in cancer trials. When planning a trial, one essential step is the calculation of a sample size, which will allow a reasonable chance (power) of detecting a pre-specified difference (effect size) at a given level of statistical significance. It is almost mandatory to include this calculation in research protocols. Many researchers quote means and standard deviations to determine effect sizes, and assume the data will have a Normal distribution to calculate their required sample size. We have investigated the distribution of scores for two commonly used HRQoL instruments completed by lung cancer patients, and have established that scores do not have the Normal distribution form. We demonstrate that an assumption of Normality can lead to unrealistically sized studies. Our recommendation is to use a technique that is based on the fact that the HRQoL data are ordinal and makes minimal but realistic assumptions. (+info)
Who's afraid of Thomas Bayes?
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Sometimes direct evidence is so strong that a prescription for practice is decreed. Usually, things are not that simple-leaving aside the possibility that important trade offs may be involved, direct comparative data may be imprecise (especially in crucial sub-groups) or subject to possible bias, or there may be no direct comparative evidence; but still decisions have to be made. In these circumstances, indirect evidence-the plausibility of effects-enters the frame. But how should we describe the extent of plausibility and, having done so, how can this be integrated with any direct evidence that might exist. Also, how can allowance be made in a transparent (that is, explicit) way for perceptions of the size of bias in the direct evidence. Enter the Reverend Thomas Bayes; plausibility (however derived-laboratory experiment, qualitative study or just "experience") is captured numerically as degrees of belief ("prior" to the direct data) and updated (by the direct evidence) to yield "posterior" probabilities for use in decision making. The mathematical model used for this purpose must explicitly take account of assumptions about bias in the direct data. This paradigm bridges theory and practice, and provides the intellectual scaffold for those who recognise that (numerically definable) probabilities, and values (also numerically definable) underlie decisions, but who also realise that subjectivity is ineluctable in science. (+info)
The role of adjuvant combination chemotherapy after cystectomy in locally advanced bladder cancer: what we do not know and why.
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BACKGROUND: Radical cystectomy is the standard treatment for patients with muscle invasive bladder cancer. Three to four cycles of adjuvant chemotherapy is widely used in patients with pT3-pT4a and/or pN+ M0 disease in an effort to delay recurrence and prolong survival. Although a number of clinical trials have been carried out, this paper questions whether the use of adjuvant combination chemotherapy is actually justified. PATIENTS AND METHODS: A review of published randomized trials of adjuvant cisplatin-containing combination chemotherapy in locally advanced bladder cancer was undertaken. Four trials including a total of 278 randomized patients were identified. RESULTS: Although these trials appear to show a significant difference in favor of adjuvant chemotherapy, serious methodological flaws were found. They have major deficiencies in terms of sample size, early stopping of patient entry, statistical analyses, reporting of results and drawing conclusions. CONCLUSIONS: These trials provide insufficient evidence to support the routine use of adjuvant chemotherapy in clinical practice due to small sample sizes, confusing analyses and terminology, and the reporting of questionable conclusions. Analyses of the duration of survival were either not done or were inconclusive and quality of life has not been considered. New large scale, multicenter trials are imperative in order to provide convincing results. (+info)
Amblyopic deficits in detecting a dotted line in noise.
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We compared detectability of a dotted line masked by random-dot noise for the amblyopic versus non-amblyopic eye of two strabismic amblyopes. Small but consistent deficits in the amblyopic eye of these observers were found, and shown to be limited to dotted-line targets composed of greater than seven dots (with performance being normal for targets of less than seven dots). These deficits were unrelated to impaired visual acuity, impaired sensitivity to dot density, and differential positional uncertainty between the eyes of our observers. The deficits were also unlikely to be due to CSF losses due to abnormal low-spatial-frequency filters involved in detecting long chains of collinear dots. Instead, the results of simulations indicate that the inefficiency in utilising large numbers of dots is due to deficits of global, integrative processes in strabismic amblyopes. These simulations also show that while neither undersampling nor positional uncertainty of inputs into integrative processes can themselves account for the amblyopic deficits, if such abnormal inputs lead to the development of stunted integrative processes then impaired sensitivity to long chains of collinear dots is indeed predicted. (+info)
General equations for Pt, Ps, and the power of the TDT and the affected-sib-pair test.
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Several equations are highlighted here, whose algebraic symmetries and generality make them very useful for understanding and comparing the properties of the transmission disequilibrium test (TDT) and affected sib-pair test. Methods using the equations are also presented that yield precise estimates of sample sizes needed for genome scans or for testing a single candidate gene, and these power methods are shown to compare favorably with alternative approaches recently described by Knapp (1999) and by Tu and Whittemore (1999). Simple relationships are also noted that summarize the relative sample sizes required for equivalent power to detect association by the TDT or case-control designs. As single-nucleotide polymorphism (SNP) maps revolutionize the search for disease-causing genes, the equations should prove useful for planning and evaluating studies of linkage and association across a broad range of possible disease models and relationships between markers and linked disease loci. (+info)
Finding the most powerful measures of the effectiveness of tissue plasminogen activator in the NINDS tPA stroke trial.
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BACKGROUND AND PURPOSE: We sought to identify the most powerful binary measures of the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) rTPA Stroke Trial. METHODS: Using the Classification and Regression Tree (CART) algorithm, we evaluated binary cut points and combination of binary cut points with the 4 clinical scales and head CT imaging measures in the NINDS tPA Stroke Trial at 4 times after treatment: 2 hours, 24 hours, 7 to 10 days, and 3 months. The first analysis focused on detecting evidence of "early activity" of tPA with the use of outcome measures derived from the 2-hour and 24-hour clinical and radiographic measures. The second analysis focused on longer-term outcome and "efficacy" and used outcome measures derived from 7- to 10-day and 3-month measures. After identifying the cut points with the ability to classify patients into the tPA and placebo groups using part I data from the trial, we then used data from part II of the trial to validate the results. RESULTS: Of the 5 most powerful outcome measures for early activity of tPA, 4 involved the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours or changes in the NIHSS score from baseline to 24 hours. The best overall single outcome measure was an NIHSS score +info)
Mutation analysis of the entire mitochondrial genome using denaturing high performance liquid chromatography.
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In patients with mitochondrial disease a continuously increasing number of mitochondrial DNA (mtDNA) mutations and polymorphisms have been identified. Most pathogenic mtDNA mutations are heteroplasmic, resulting in heteroduplexes after PCR amplification of mtDNA. To detect these heteroduplexes, we used the technique of denaturing high performance liquid chromatography (DHPLC). The complete mitochondrial genome was amplified in 13 fragments of 1-2 kb, digested in fragments of 90-600 bp and resolved at their optimal melting temperature. The sensitivity of the DHPLC system was high with a lowest detection of 0.5% for the A8344G mutation. The muscle mtDNA from six patients with mitochondrial disease was screened and three mutations were identified. The first patient with a limb-girdle-type myopathy carried an A3302G substitution in the tRNA(Leu(UUR)) gene (70% heteroplasmy), the second patient with mitochondrial myopathy and cardiomyopathy carried a T3271C mutation in the tRNA(Leu(UUR)) gene (80% heteroplasmy) and the third patient with Leigh syndrome carried a T9176C mutation in the ATPase6 gene (93% heteroplasmy). We conclude that DHPLC analysis is a sensitive and specific method to detect heteroplasmic mtDNA mutations. The entire automatic procedure can be completed within 2 days and can also be applied to exclude mtDNA involvement, providing a basis for subsequent investigation of nuclear genes. (+info)