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Haplotype sharing analysis using mantel statistics.

OBJECTIVE: The potential value of haplotypes has attracted widespread interest in the mapping of complex traits. Haplotype sharing methods take the linkage disequilibrium information between multiple markers into account, and may have good power to detect predisposing genes. We present a new approach based on Mantel statistics for spacetime clustering, which is developed in order to improve the power of haplotype sharing analysis for gene mapping in complex disease. METHODS: The new statistic correlates genetic similarity and phenotypic similarity across pairs of haplotypes for case-only and case-control studies. The genetic similarity is measured as the shared length between haplotypes around a putative disease locus. The phenotypic similarity is measured as the mean-corrected cross-product based on the respective phenotypes. We analyzed two tests for statistical significance with respect to type I error: (1) assuming asymptotic normality, and (2) using a Monte Carlo permutation procedure. The results were compared to the chi(2) test for association based on 3-marker haplotypes. RESULTS: The results of the type I error rates for the Mantel statistics using the permutational procedure yielded pointwise valid tests. The approach based on the assumption of asymptotic normality was seriously liberal. CONCLUSION: Power comparisons showed that the Mantel statistics were better than or equal to the chi(2) test for all simulated disease models.

Case-Control Studies↗

Compartments within the lymph node cortex of calves and adult cattle differ in the distribution of leukocyte populations: an immunohistochemical study using computer-assisted morphometric analysis.

The combination of an immunohistochemical technique and a panel of monoclonal antibodies was used to investigate the presence of leukocyte populations in the distal jejunal lymph node of 3-4 week old calves and adult cattle. The application of computer-assisted morphometric analysis enabled information to be obtained on the distribution of leukocyte populations in lymphoid compartments of the lymph node cortex. Semi-quantitative estimates of the areas of staining in histological sections showed that calves possessed significantly fewer B-cells and CD4+ cells in the outer cortex and significantly fewer T-cells (CD4+, CD8+ and gamma delta T-cells) in the deep cortex. These findings were interpreted to be a possible consequence of immunosuppression resulting from the passive transfer of maternal immunity in colostrum. The presence of some B-cell follicles in the region defined as the deep cortex suggested the on-going differentiation of this predominantly T-cell compartment. The larger presence of interdigitating cells (IDC) in the deep cortex of calves than adults was suggested by significantly larger CD1+ populations and it was argued that this could be the result of the confrontation with exogenous antigen faced by calves in early postnatal life. Antigen presenting populations, pan MHC II+ and MHC II DQ+ populations, were increased in all compartments of calf lymph nodes but were not significantly different from the populations in adult lymph nodes. Variance component analysis of the data generated in the present study showed that the image analysis technique was an effective and statistically powerful approach to investigate leukocyte populations within the specific microenvironments of the lymph node.

Age Factors↗

Life-table methods for contraceptive research.

Life-table methods used for the analysis and interpretation of contraceptive follow-up studies differ from those used in other areas of medical research. The historical development of these methods in the contraceptive literature is outlined and the two main methods are discussed, compared and shown to differ mainly in their nomenclature; their results are very similar in practice. The daily life-table method is simpler to apply and interpret, and facilitates analysis using the logrank statistic as well as powerful regression modelling techniques for survival data.

Actuarial Analysis↗

Agreement of two different methods for measurement of heart rate variability.

BACKGROUND: The widespread use of affordable devices with sufficient precision for measurement of heart rate variability (HRV) might lead to early detection of abnormalities in a large number of high-risk patients and athletes. The purpose of this study was to determine the limits of agreement of two devices for measuring HRV parameters differing in price and assumed precision. SUBJECTS AND METHODS: 36 healthy subjects (22 men and 14 women) with a mean age of 27.4 (SD 11.1) years were included. The two devices used for comparison were PowerLab with Chart software as the reference golden standard, and Polar Transmitter/Advantage with Precision Performance software, respectively. Measurements included the following heart rate variability parameters: heart rate, range of R-R-interval duration, SDNN, rMSSD, total Power, VLF power, LF power, and HF power. Measurements were taken during metronomic respiration over a total period of 3 minutes. Statistical analysis was performed according to Bland and Altman and by means of scatterplots and Spearman correlation coefficients. RESULTS: Good agreement was found for heart rate (95 % CI of limits of agreement: -0.7-0.6 bpm; r = 0.999), range of duration of R-R-intervals (95 % CI: -18.9-17.0 ms; r = 0.997), rMSSD (95 % CI: -1.5-2.5 ms; r = 0.999), and SDNN (95 % CI: -3.0-3.1 ms; r = 0.997). Correlation of measurements was high for the variables total Power, VLF power, LF power, and HF power. Analysis of method agreement for frequency domain variables was statistically not feasible. CONCLUSION: The level of agreement for the analyzed time domain variables between the reference golden standard and the inexpensive device is sufficient to permit initial screening by family doctors, and self-administration by high-risk patients and athletes.

Adult↗

Overexpression of cyclin A overrides the effect of p53 alterations in breast cancer patients with long follow-up time.

The tumour suppressor gene p53 and its protein controls critical cellular functions in cell cycle regulation as well as in apoptosis. Recently, in an in vitro study on breast cancer cell line MCF-7, the apoptotic function of p53 has been shown to be altered by overexpression of cyclin A. In this study we have demonstrated a similar association in a consecutive series of 166 breast cancer patients operated for invasive breast carcinomas. We detected mutations (exon 5-8) in the tumour tissue from 28 (16.0%) of the patients, and positive immunoreactivity of p53 protein was detected in tumour tissue samples from 32 (18.8%) patients. A statistically significant correlation between TP53 gene mutations and positive immunohistochemistry of p53 protein was observed (p = 0.0038). Mutations of the TP53 gene, as well as positive immunoreactivity to p53, were associated with poor prognosis (mutations p = 0.053, HR = 1.8, 95% CI 0.99-3.4; positive immunoreactivity p = 0.029, HR 1.33, 95% CI 1.0-1.7; mutation and/or positive immunoreactivity p = 0.015, HR 2.1, 95% CI 1.2-3.7) when cyclin A was not included in the survival analysis. However, when cyclin A overexpression was included, alteration of the p53 protein (mutations and/or positive immunoreactivity) lost its statistical power (p = 0.088). In a stratified survival analysis the OR fell from 3.0 (95% CI 1.2-8.3, p = 0.03) in the low-expression cyclin A stratum to 1.3 (95% CI 0.42-4.1, p = 0.77) in the overexpression cyclin A stratum.

Adult↗

An improved statistical methodology to estimate and analyze impedances and transfer functions.

Estimating the mathematical relationship between pulsatile time series (e.g., pressure and flow) is an effective technique for studying dynamic systems. The frequency-domain relationship between time series, often calculated as an impedance (pressure/flow), is known more generally as a frequency-response or transfer function (output/input). Current statistical methods for transfer function analysis 1) assume erroneously that repeated observations on a subject are independent, 2) have limited statistical value and power, or 3) are restricted to use in single subjects rather than in an entire sample. This paper develops a regression model for transfer function analysis that corrects each of these deficiencies. Spectral densities of the input and output time series and the cross-spectral density between them are first estimated from discrete Fourier transforms and then used to obtain regression estimates of the transfer function. Statistical comparisons of the transfer function estimates use a test statistic that is distributed as chi2. Confidence intervals for amplitude and phase can also be calculated. By correctly modeling repeated observations on each subject, this improved statistical approach to transfer function estimation and analysis permits the simultaneous analysis of data from all subjects in a sample, improves the power of the transfer function model, and has broad relevance to the study of dynamic physiological systems.

Blood Pressure↗

Linkage detection under heterogeneity and the mixture problem.

Linkage analysis has contributed to the localization of many human disease genes. The presence of locus heterogeneity reduces statistical power and can prejudice the detection of linkage if the analysis assumes homogeneity. Nevertheless, mixed genetic models are not routinely used in gene searches. The null distribution of the test statistic is not uniquely defined. In this paper, a transformation is used to determine an approximate asymptotic distribution of the test statistic under a mixture model. The equivalent critical values of the test are computed and the performance of the test under various levels of heterogeneity and family size is investigated. For gene searches, we recommend the routine use of an admixture model with a critical lod score of 3.44.

Algorithms↗

Exploiting the full power of temporal gene expression profiling through a new statistical test: application to the analysis of muscular dystrophy data.

BACKGROUND: The identification of biologically interesting genes in a temporal expression profiling dataset is challenging and complicated by high levels of experimental noise. Most statistical methods used in the literature do not fully exploit the temporal ordering in the dataset and are not suited to the case where temporal profiles are measured for a number of different biological conditions. We present a statistical test that makes explicit use of the temporal order in the data by fitting polynomial functions to the temporal profile of each gene and for each biological condition. A Hotelling T2-statistic is derived to detect the genes for which the parameters of these polynomials are significantly different from each other. RESULTS: We validate the temporal Hotelling T2-test on muscular gene expression data from four mouse strains which were profiled at different ages: dystrophin-, beta-sarcoglycan and gamma-sarcoglycan deficient mice, and wild-type mice. The first three are animal models for different muscular dystrophies. Extensive biological validation shows that the method is capable of finding genes with temporal profiles significantly different across the four strains, as well as identifying potential biomarkers for each form of the disease. The added value of the temporal test compared to an identical test which does not make use of temporal ordering is demonstrated via a simulation study, and through confirmation of the expression profiles from selected genes by quantitative PCR experiments. The proposed method maximises the detection of the biologically interesting genes, whilst minimising false detections. CONCLUSION: The temporal Hotelling T2-test is capable of finding relatively small and robust sets of genes that display different temporal profiles between the conditions of interest. The test is simple, it can be used on gene expression data generated from any experimental design and for any number of conditions, and it allows fast interpretation of the temporal behaviour of genes. The R code is available from V.V. The microarray data have been submitted to GEO under series GSE1574 and GSE3523.

Animals↗

Statistical analysis of noise-induced multiple filamentation.

The propagation of high-power large-aperture laser beams in a Kerr medium is considered. A statistical approach is developed for the growth of filaments from small-amplitude small-scale initial modulations. Closed-form expressions are derived for the intensity distribution, contrast, and maximal beam intensity, which are valid up to the blowup of the most intense filament. Numerical experiments are found to be in good agreement with theoretical predictions.

Journal Article↗

Seven ways to increase power without increasing N.

Many readers of this monograph may wonder why a chapter on statistical power was included. After all, by now the issue of statistical power is in many respects mundane. Everyone knows that statistical power is a central research consideration, and certainly most National Institute on Drug Abuse grantees or prospective grantees understand the importance of including a power analysis in research proposals. However, there is ample evidence that, in practice, prevention researchers are not paying sufficient attention to statistical power. If they were, the findings observed by Hansen (1992) in a recent review of the prevention literature would not have emerged. Hansen (1992) examined statistical power based on 46 cohorts followed longitudinally, using nonparametric assumptions given the subjects' age at posttest and the numbers of subjects. Results of this analysis indicated that, in order for a study to attain 80-percent power for detecting differences between treatment and control groups, the difference between groups at posttest would need to be at least 8 percent (in the best studies) and as much as 16 percent (in the weakest studies). In order for a study to attain 80-percent power for detecting group differences in pre-post change, 22 of the 46 cohorts would have needed relative pre-post reductions of greater than 100 percent. Thirty-three of the 46 cohorts had less than 50-percent power to detect a 50-percent relative reduction in substance use. These results are consistent with other review findings (e.g., Lipsey 1990) that have shown a similar lack of power in a broad range of research topics. Thus, it seems that, although researchers are aware of the importance of statistical power (particularly of the necessity for calculating it when proposing research), they somehow are failing to end up with adequate power in their completed studies. This chapter argues that the failure of many prevention studies to maintain adequate statistical power is due to an overemphasis on sample size (N) as the only, or even the best, way to increase statistical power. It is easy to see how this overemphasis has come about. Sample size is easy to manipulate, has the advantage of being related to power in a straight-forward way, and usually is under the direct control of the researcher, except for limitations imposed by finances or subject availability. Another option for increasing power is to increase the alpha used for hypothesis-testing but, as very few researchers seriously consider significance levels much larger than the traditional .05, this strategy seldom is used. Of course, sample size is important, and the authors of this chapter are not recommending that researchers cease choosing sample sizes carefully. Rather, they argue that researchers should not confine themselves to increasing N to enhance power. It is important to take additional measures to maintain and improve power over and above making sure the initial sample size is sufficient. The authors recommend two general strategies. One strategy involves attempting to maintain the effective initial sample size so that power is not lost needlessly. The other strategy is to take measures to maximize the third factor that determines statistical power: effect size.

Data Interpretation, Statistical↗

Meta-analysis of genome searches.

We have developed a method for meta-analysis of genome scans which allows systematic integration of data from published results. The Genome Search Meta-analysis method (GSMA) uses a non-parametric ranking method to identify genetic regions that show consistently increased sharing statistics or lod scores. The GSMA ranks genetic regions according to the lod score or p-value achieved in each scan. The summed rank across studies is compared to its probability distribution assuming ranks are randomly assigned. The GSMA can confirm evidence for regions highlighted in the original genome scans, and identify novel regions, which did not reach significance in any scan. In this paper, the GSMA was applied to four genome screens in multiple sclerosis and across 11 screens from autoimmune disorders. The GSMA is appropriate for studies with different family ascertainment, markers, and statistical analysis methods. The method increases the power to detect individual linkages in a clinically homogeneous dataset and has the potential to detect susceptibility loci in clinically distinct diseases which show involvement of common pathogenetic pathways.

Autoimmune Diseases↗

A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability.

The statistical test of hypothesis of no difference between the average bioavailabilities of two drug formulations, usually supplemented by an assessment of what the power of the statistical test would have been if the true averages had been inequivalent, continues to be used in the statistical analysis of bioavailability/bioequivalence studies. In the present article, this Power Approach (which in practice usually consists of testing the hypothesis of no difference at level 0.05 and requiring an estimated power of 0.80) is compared to another statistical approach, the Two One-Sided Tests Procedure, which leads to the same conclusion as the approach proposed by Westlake based on the usual (shortest) 1-2 alpha confidence interval for the true average difference. It is found that for the specific choice of alpha = 0.05 as the nominal level of the one-sided tests, the two one-sided tests procedure has uniformly superior properties to the power approach in most cases. The only cases where the power approach has superior properties when the true averages are equivalent correspond to cases where the chance of concluding equivalence with the power approach when the true averages are not equivalent exceeds 0.05. With appropriate choice of the nominal level of significance of the one-sided tests, the two one-sided tests procedure always has uniformly superior properties to the power approach. The two one-sided tests procedure is compared to the procedure proposed by Hauck and Anderson.

Biological Availability↗

Corneal topographic changes after transconjunctival (25-gauge) sutureless vitrectomy.

PURPOSE: To evaluate the topographic changes in the cornea after pars plana vitrectomy (PPV) with 25-gauge transconjunctival sutureless vitrectomy (TSV) system. DESIGN: Prospective, interventional case series. METHODS: In this prospective study, we evaluated the topographic changes of the cornea in 32 eyes of 32 patients who underwent PPV with the 25-gauge TSV system. The topographic parameters that were analyzed statistically were the average corneal power, corneal surface cylinder, surface asymmetry index, and surface regularity index. Mean induced astigmatism was estimated by vector analysis software. Wilcoxon test was used for statistical analysis. RESULTS: There was no significant change in average corneal power, corneal surface cylinder, surface asymmetry index, and surface regularity index parameters at first day, first week, and first month after the operation. Mean induced astigmatism was 0.38 diopters at 15 degrees. CONCLUSIONS: Corneal surface and astigmatic changes were observed to be insignificant in the early postoperative period after PPV with the 25-gauge TSV system.

Aged↗

Power dressing and meta-analysis: incorporating power analysis into meta-analysis.

AIMS: This paper highlights the lack of consideration that is given to power in the health and social sciences, which is a continuing problem with both single study research and more importantly for meta-analysis. BACKGROUND: The power of a study is the probability that it will lead to a statistically significant result. By ignoring power the single study researcher makes it difficult to get negative results published and therefore affects meta-analysis through publication bias. Researchers using meta-analysis, who also ignore power, then compound the problem by including studies with low power that are more likely to show significant effects. METHOD: A simple means of calculating an easily understood measure of effect size from a contingency table is demonstrated in this paper. A computer programme for determining the power of a study is recommended and a method of reflecting the adequacy of the power of the studies in a meta-analysis is suggested. An example of this calculation from a meta-analytic study on intravenous magnesium, which produced inaccurate results, is provided. CONCLUSION: It is demonstrated that incorporating power analysis into this meta-analysis would have prevented misleading conclusions being reached. Some suggestions are made for changes in the protocol of meta-analytic studies, which highlight the importance of power analysis.

Bias↗

Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials.

To evaluate the results of autologous stem cell transplantation (ASCT) in a large population of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR), we performed an individual data-based overview of the last three trials from the LALA group. Overall, 349 patients with ALL prospectively randomized in the consecutive LALA-85, -87, and -94 trials to receive either ASCT or chemotherapy as post-CR treatment were analyzed. Eligibility criteria were 15-50-year-old patients without sibling donors in both LALA-85/87 trials and 15-55-year-old patients with high-risk ALL and no sibling donors in the LALA-94 trial. Intent-to-treat analysis, which compared 175 patients from the ASCT arm to 174 patients from the chemotherapy arm, showed that ASCT was associated with a lower cumulative incidence of relapse (66 vs 78% at 10 years; P=0.05), without significant gain in disease-free or overall survival. Despite a possible lack of statistical power, a nested case-control analysis performed in 85 patient pairs adjusted for time to transplant and prognostic covariates confirmed these intent-to-treat results in patients actually transplanted. Of interest, the reduced relapse risk after ASCT translated in better disease-free survival in the 300 rapid responders who reached CR after the first induction course.

Adult↗

Reporting and interpreting adjuvant therapy clinical trials. International Breast Cancer Study Group (formerly Ludwig Group).

Identifying effective adjuvant treatments for patients with node-negative breast cancer is made difficult by the heterogeneity of the disease, the relatively low event rate and long follow-up time required, and the small magnitude of effects of current therapies. Several aspects of clinical trials that influence the appropriate reporting and interpretation of statistical results are discussed. We point out that the P value is a measure of the statistical uncertainty of an observed outcome and depends on the number of events available for analysis; it is not a measure of the magnitude of a treatment effect. We recommend that the relative reduction in the risk of an event and its 95% confidence interval be presented as an estimate of the treatment effect size, and that absolute improvements be used to judge whether treatment benefits outweigh the costs for the patient population. We suggest that subgroup analyses are important to define treatment effects within groups with different prognoses, and should be used with the understanding that multiple comparisons increase the chance of a false-positive result. Subgroup analysis should rely on the estimates of relative treatment effect and should avoid the use of the P value to declare incorrectly that "treatment is effective for one subgroup but not for another." We present the meta-analysis (overview) as a powerful method to demonstrate the statistical significance of a modest treatment effect by increasing the number of events available for analysis. The interpretation of overviews should consider the potential for treatment interactions and the validity of indirect comparisons that are not protected by a randomized design.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗

Multivariate linkage analysis using the electrophysiological phenotypes in the COGA alcoholism data.

Multivariate linkage analysis using several correlated traits may provide greater statistical power to detect susceptibility genes in loci whose effects are too small to be detected in univariate analysis. In this analysis, we apply a new approach and perform a linkage analysis of several electrophysiological phenotypes of the Collaborative Study on the Genetics of Alcoholism data of the Genetic Analysis Workshop 14. Our approach is based on a variance-component model to map candidate genes using repeated or longitudinal measurements. It can take into account covariate effects and time-dependent genetic effects in general pedigree data. We compare our results with the ones obtained by SOLAR using single measurement data. Our multivariate linkage analysis found linkage evidence on two regions on chromosome 4: around marker GABRB1 at 51.4 cM and marker FABP2 at 116.8 cM (unadjusted p-value = 0.00006).

Alcoholism↗

Results of a United States and Soviet Union joint project on nervous system effects of microwave radiation.

During the course of a formal program of cooperation between the United States and the Soviet Union concerning the biological effects of physical factors in the environment, it was concluded that duplicate projects should be initiated with the general goal of determining the most sensitive and valid test procedures for evaluating the effects of microwave radiation on the central nervous system. This report details an initial step in this direction. Male rats of the Fischer 344 strain were exposed or sham exposed to 10 mW/cm2 continuous wave microwave radiation at 2.45 GHz for a period of 7 hr. Animals were subjected to behavioral, biochemical, or electrophysiological measurements during and/or immediately after exposure. Behavioral tests used were passive avoidance and activity in an open field. Biochemical measurements were ATPase (Na+, K+; Mg2+, Ca2+) and K+ alkaline phosphatase activities. Electrophysiological measurements consisted of EEG frequency analysis. Neither group observed a significant effect of microwave irradiation on open field activity. Both groups observed changes in variability of the data obtained using the passive avoidance procedure, but not in the same parameters. The U.S. group, but not the USSR group, found significantly less Na+,K+-ATPase activity in the microwave-exposed animals compared to the sham exposed animals. Both groups found incidences of statistically significant effects in the power spectral analysis of EEG frequency, but not at the same frequency. The failure of both groups to substantiate the results of the other reinforces our contention that such duplicate projects are important and necessary.

Adenosine Triphosphatases↗