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A comparison of multivariable mathematical methods for predicting survival--III. Accuracy of predictions in generating and challenge sets.

This paper concludes a study of "performance variability" when four methods of multivariable analysis--multiple linear regression, discriminant function analysis, multiple logistic regression, and two arrangements of Cox's proportional hazards regression--were applied to the same stratified random samples of "generating sets" containing seven different statistical distributions of cogent biologic attributes in a composite staging system for a large cohort of patients with lung cancer. Each model developed from the generating sets was also applied for predictions in a previously sequestered "challenge set". Across the different generating sets, the multivariable methods showed good agreement with one another in the stepwise choice of first two powerful predictor variables, but not in the sequence of subsequent choices or in the standardized coefficients assigned to the same collection of "forced" variables. In concordance of predictions for individual patients in the generating sets, the overall proportions of disagreement for pairs of methods ranged from 0 to 28%, and kappa values ranged from 0.49 to 1.00. The accuracy of individual predictions showed relatively similar results when the different methods were applied to the same generating set. Across the generating sets, the different methods showed similar total results but substantial variations in predictions for alive and dead patients. When the models from the generating sets were applied for predictions in the challenge set, the results showed an analogous pattern: similar accuracy within models for overall and live/dead predictions, but substantial variations in live/dead predictions across models derived from different generating sources. The results showed that the multivariable methods often had good agreement with one another in predictions for groups but not for individual persons; and that no single method was superior to the others or to the composite staging system. We conclude that multivariable analytic methods may be most effective and consistent if used to find the few most powerful predictor variables, omitting the many other variables that may be "statistically significant" but less cogent. The powerful predictors may sometimes be best constructed, before the analysis begins, as composite variables containing appropriate unions or ordinal arrangements of elemental candidate variables.

Cohort Studies↗

The economics of basiliximab (Simulect) in preventing acute rejection in renal transplantation.

An economic evaluation was undertaken alongside a multicentre international trial of basiliximab. Resource usage within the trial was assessed, and the cost implications of using basiliximab evaluated. Recipients of a primary cadaveric kidney transplant were recruited into a double-blind trial and received either placebo ( n=186) or basiliximab ( n=190). Clinical outcomes and resource usage were monitored in the 12 months following transplantation. Local unit costs were obtained, and global analysis was undertaken using health sector purchasing-power parity rates. No statistically significant differences were found in the mean cost of treatment per patient. The mean cost of treatment was US$47,940 for basiliximab patients and US$46,280 for placebo patients, a mean difference of US$1,660 (95% confidence interval (CI): -US$4,150, US$7,360; P=0.58). Basiliximab produces clinical benefit in terms of preventing episodes of acute rejection, whilst the difference in the total resource usage and cost of treatment is not statistically significant.

Analysis of Variance↗

Spectral analysis of full field digital mammography data.

The spectral content of mammograms acquired from using a full field digital mammography (FFDM) system are analyzed. Fourier methods are used to show that the FFDM image power spectra obey an inverse power law; in an average sense, the images may be considered as 1/f fields. Two data representations are analyzed and compared (1) the raw data, and (2) the logarithm of the raw data. Two methods are employed to analyze the power spectra (1) a technique based on integrating the Fourier plane with octave ring sectioning developed previously, and (2) an approach based on integrating the Fourier plane using rings of constant width developed for this work. Both methods allow theoretical modeling. Numerical analysis indicates that the effects due to the transformation influence the power spectra measurements in a statistically significant manner in the high frequency range. However, this effect has little influence on the inverse power law estimation for a given image regardless of the data representation or the theoretical analysis approach. The analysis is presented from two points of view (1) each image is treated independently with the results presented as distributions, and (2) for a given representation, the entire image collection is treated as an ensemble with the results presented as expected values. In general, the constant ring width analysis forms the foundation for a spectral comparison method for finding spectral differences, from an image distribution sense, after applying a nonlinear transformation to the data. The work also shows that power law estimation may be influenced due to the presence of noise in the higher frequency range, which is consistent with the known attributes of the detector efficiency. The spectral modeling and inverse power law determinations obtained here are in agreement with that obtained from the analysis of digitized film-screen images presented previously. The form of the power spectrum for a given image is approximately l/f2beta with beta approximately 1.4-1.5.

Biophysical Phenomena↗

MTHFR C677T and colorectal cancer risk: A meta-analysis of 25 populations.

The common functional methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may influence the risk of colorectal cancer (CRC), but data from published studies with individually low statistical power are conflicting. To clarify the role of MTHFR C677T genotype in CRC, we considered all available studies in a meta-analysis. Studies reporting on MTHFR C677T genotype and CRC were searched in PubMed up to April 2006. The principle prior hypothesis was that homozygosity for MTHFR 677TT would be associated with reduced risk of CRC. Data were available for 29,931 subjects, including 12,243 with CRC, from 25 independent populations. Compared to the homozygous CC genotype, the MTHFR 677TT genotype was associated with a reduced risk of CRC (odds ratio (OR): 0.83; 95% confidence interval (CI): 0.75-0.93; p = 0.001). There was some heterogeneity among the results of individual studies, but this was not statistically significant (heterogeneity p = 0.12; I2 = 25.8%). Heterozygosity for MTHFR 677 did not influence CRC risk (OR: 0.99; 95% CI: 0.94-1.04). These findings indicate that individuals homozygous for the MTHFR 677TT genotype are at moderately reduced risk of CRC, and support the proposal that common genetic variation in the MTHFR gene contributes to CRC susceptibility, probably accounting for at least 9% of the total incidence.

Adult↗

Harvesting the radial artery: does it affect early postoperative hand function?

BACKGROUND: The radial artery (RA) is increasingly being used as a conduit for coronary artery bypass grafting. Previous studies have demonstrated that there is no significant deterioration in hand function in the long term. The aim of this study was to assess whether removal of the RA caused any alteration in the function or power of the hand 5 days postoperatively that would affect the patient's ability for self care on returning home. METHODS: A consecutive series of 37 patients undergoing RA harvesting was assessed over a period of 12 months from August 2000 to July 2001 as part of a prospective controlled trial. Grip power and fine motor skills in the operated hand were assessed preoperatively with an elasticated grip strength tester and an 18-hole peg board. This test was repeated 5 days postoperatively. The results were analyzed with a paired-sample t test to assess whether there was a significant difference between preoperative and postoperative hand function. RESULTS: The analysis showed that there was no statistically significant difference in fine motor function or grip power following surgery to harvest the RA. CONCLUSION: This study provides evidence to suggest that the RA can be safely harvested for use as a conduit in coronary artery bypass grafting, with no significant short-term deterioration in hand function.

Aged↗

Comparing automatic and manual image processing in FLARE assay analysis for colon carcinogenesis.

Measurement of the amount of oxidative damage to DNA is one tool that can be used to estimate the beneficial effect of diet on the prevention of colon carcinogenesis. The FLARE assay is a modification of the single-cell gel electrophoresis (Comet) assay, and provides a measure of the 8OHdG adduct in the cells. In this paper, we present two innovations to the existing methods of analysis. The first one is related to the FLARE assay itself. We describe automated image analysis techniques that can be expected to measure oxidative damage faster, reproducibly, with less noise, and hence achieve greater statistical power. The proposed technique is compared to an existing technique, which was more manual and thus slower. The second innovation is our statistical analysis: we exploit the shape of FLARE intensity histograms, and show statistically significant diet effects in the duodenum. Previous analyses of this data concentrated on simple summary statistics, and found only marginally statistically significant diet effects. With the new imaging method and measure of oxidative damage, we show cells in the duodenum exposed to fish oil as having more oxidative damage than cells exposed to corn oil.

Journal Article↗

Comparison of model-free linkage mapping strategies for the study of a complex trait.

We compared several strategies for identifying and estimating effects from a genetic locus in the etiology of a complex trait. For our analyses we used data from simulated trait 1 and chromosome 5. Results from analysis of the first 20 replicates showed that a components of variance test provided considerably better power for identifying linkage than tests that consider pair differences. We also compared the power from constructing tests with a single marker, an approximate method using five markers jointly, or a multipoint analysis using all 25 markers on chromosome 5 jointly. Results from this analysis showed substantially better power when all markers were jointly used in the analysis. Results from considering all replicates showed that all methods of estimation provided maximal test statistics at the correct marker position, but the components of variance procedure provided more power to detect the correct position than other methods.

Analysis of Variance↗

Association studies of QTL for multi-allele markers by mixed models.

In this paper, we extend association study methods of both Fan et al. [Hum Hered 2002;53:130-145], in which a quantitative trait locus (QTL) and a multi-allele marker are considered for trio families, and Fan and Xiong [Biostatistics 2003, in press], in which a QTL and a bi-allelic marker are considered for nuclear families. The objective is to build mixed models for association study between a QTL and a multi-allelic marker for nuclear families with any number of offspring. Two types of nuclear family data are considered: the first is genetic data of offspring from at least one heterozygous parents, and the second is genetic data of offspring of nuclear family. (1) For the data of offspring from at least one heterozygous parents, we assume that at least one parent is heterozygous at the marker locus, and we may infer clearly the transmission of parental marker alleles to the offspring. We show that it can be used in association study in the presence of linkage. The theoretical basis is the difference between the conditional mean of trait value given an allele is transmitted and the conditional mean of trait value given the allele is not transmitted from a heterozygous parent. To build valid models, we calculate the variance covariance structure of trait values of offspring. Besides, the reduction of the number of parameters is discussed under an assumption of tight linkage between the trait locus and the marker. (2) For the data of offspring of nuclear family, we show that it can be used in general association study. In this case, the theoretical basis is the difference between the conditional mean of trait values given an allele is transmitted from a parent and the population mean. Then, we calculate variance-covariance structure of trait values of offspring. (3) Based on the theoretical analysis, mixed models are built for each type of the data, and related test statistics are proposed for association study. By power calculation and comparison, we show that, in some instances, the proposed test statistics have higher power than that by collapsing alleles to be new ones. The proposed models are used to analyze chromosomes 4 and chromosome 16 data of the Oxford asthma data, Genetic Analysis Workshop 12.

Asthma↗

The clinical value of ultrasonic tissue characterization in the management of heart transplant patients.

The purpose of this study was to evaluate the rejection process by ultrasonic tissue characterization. Serial 2D echocardiographic images were obtained within 24 h prior to an endomyocardial biopsy. The end-diastolic echoframes were digitized into a computer matrix. A region of interest was placed into the anteroseptal segment of each scan. Image texture was analysed by four major groups of texture analysis (first-order histogram, co-occurrence matrix, run-length statistic, power spectrum). In 23 patients, 408 biopsies were taken after each examination, so that correlation between the ultrasonic tissue measurements and the histological state of the tissue could be determined. When rejection occurred, heterogeneity, brightness and contrast of texture increased. Of 117 texture parameters originally claculated, three parameters (inverse difference moment, run-length non-uniformity, ring sums of power spectrum) that characterized rejection were determined by means of discriminance analysis. Compared with biopsy findings, echocardiographic sensitivity for moderate rejection was 93.3% and specifity 83.6%. Our study indicates that acute rejection is associated with changes in echocardiographic texture. Serial echocardiographic texture analysis can reliably identify heart transplant rejection.

Diagnosis, Computer-Assisted↗

Developing surgical intervention criteria for thoracic aortic aneurysms.

In summary, the development of intervention criteria is a complex and challenging endeavor. Specific examination of this issue is crucial to the appropriate clinical care of patients. With these objectives in mind, we have drawn upon our clinical experience to design, by way of statistical analysis, reasoned size criteria for intervention. These intervention criteria must be carefully weighed against the patient's age, overall physical condition, and anticipated life expectancy. We have approached the development of criteria for intervention using statistical methodology from the standpoint of preventing complications (i.e., dissection and rupture). Symptomatic states, organ compression, concomitant aortic insufficiency, and acute ascending aortic dissection are well-accepted general indications for surgical intervention regardless of aortic size. The appendix incorporates the size criteria developed in the present study as an integral component within a comprehensive strategy for managing patients with TAA. This study confirms that aneurysms of the thoracic aorta are potentially lethal, that attentive follow-up is critical, and that adverse events can be anticipated based on size criteria. As we continue to expand our database, we hope to refine further statistically-based recommendations for surgical intervention. Multi-institutional patient enrollment, with the concomitant statistical power of larger patient numbers, would considerably strengthen this type of analysis.

Adolescent↗

The specific power of parentage exclusion in a child's blood relatives.

BACKGROUND: The impersonation of parent and child by two other blood relatives is an important problem in parentage analysis involving potential immigrants. STUDY DESIGN AND METHODS: A statistic (AR) is proposed, based on the specific power of exclusion of paternity, which describes the ability of a child's test results to demonstrate evidence of nonparentage under the hypothesis that an ostensible parent is actually an older sibling. A case illustrates the value of A(R): a woman and her two alleged children were typed at 3 variable number of tandem repeat (VNTR) loci after 18 short tandem repeat (STR) loci initially showed strong evidence of the woman's maternity of one child and her exclusion from parentage of the second. AR and 1 - AR were calculated from the STR types of the first child. RESULTS: The woman was excluded from maternity of both children with the additional VNTR tests. Given the 18 STR test findings of the first child, the probability was 12 percent that there would be no inconsistencies with parentage in a sibling pretending to be a parent. CONCLUSION: The value 1 - AR, siblings not excluded from parentage, explains how a seemingly large number of examined loci can fail to reveal even one genetic inconsistency if two siblings have posed as parent and child. Approximately 25 STR loci appear necessary to achieve 95 percent confidence of detecting at least one genetic inconsistency indicative of nonparentage.

Adult↗

A test of transmission/disequilibrium for quantitative traits in pedigree data, by multiple regression.

The transmission/disequilibrium (TD) test (TDT), proposed, by Spielman et al., for binary traits is a powerful method for detection of linkage between a marker locus and a disease locus, in the presence of allelic association. As a test for linkage disequilibrium, the TDT makes the assumption that any allelic association present is due to linkage. Allison proposed a series of TD-type tests for quantitative traits and calculated their power, assuming that the marker locus is the disease locus. All these tests assume that the observations are independent, and therefore they are applicable, as a test for linkage, only for nuclear-family data. In this report, we propose a regression-based TD-type test for linkage between a marker locus and a quantitative trait locus, using information on the parent-to-offspring transmission status of the associated allele at the marker locus. This method does not require independence of observations, thus allowing for analysis of pedigree data as well, and allows adjustment for covariates. We investigate the statistical power and validity of the test by simulating markers at various recombination fractions from the disease locus.

Computer Simulation↗

Clinical indicators of prognosis in unresected lung cancer.

A prognosis estimate in palliative treatment for inoperable lung cancer is thought to be of value. Performance status is now recognized as being of major importance, but only recently has been consistently available. We examined other simple information not requiring clinical or laboratory tests that is available in the clinical histories of a series of 1,839 patients with unresected lung cancer. Actuarial survivals at 1, 2, and 5 years were 21.9, 7.8, and 2.0 percent, respectively. The median survival rate was 24 weeks. Squamous cell histology and an increasing interval between the first symptoms and diagnosis were associated with a better prognosis. The number of symptoms recorded at the time of assessment had strong negative association with survival; asymptomatic patients had a two-year survival of 26 percent compared with 6 percent or less with four or more symptoms. A similar discrimination is given by Feinstein's index, which combines information on the number and type of symptoms and on the interval between first symptom and diagnosis. The clinical stage was strongly related to survival. Additional statistical analysis showed that the prognostic value of each of the most powerful prognostic factors, the number of symptoms, and Feinstein's index was little altered by the use of data on stage and histology in addition. The data show a range of median survival of 18 to 60 weeks for Feinstein's indices from 6 to 1, suggesting that the symptom index is useful particularly in the relatively well patients and the performance status particularly in those more ill. The combination may be better than either alone, and it is recommended that such information be recorded for all lung cancer patients.

Adenocarcinoma↗

[Prognostic value of Charlson comorbidity index at 30 days and 1 year after acute myocardial infarction].

INTRODUCTION AND OBJECTIVES: The Charlson comorbidity index (CCI), an indicator of comorbidity, has been used as an adjusting variable in multivariate models. Because of its prognostic value per se for cardiovascular complications after acute myocardial infarction (AMI), we sought to determine the predictive value of the CCI for all-cause mortality and recurrent AMI 30 days and 1 year after the index event. PATIENTS AND METHOD: We analyzed 1035 consecutive patients admitted with the diagnosis of AMI (ST elevation=508 and non-ST elevation=527). The composite endpoint was determined after 30 days (13.9%) and 1 year (26.3%) of follow-up. The CCI was calculated on admission, and other variables with prognostic value were also recorded. CCI was stratified in 4 categories: 1: CCI=0 (control), 2: CCI=1, 3: CCI=2,4: CCI> or =3. Cox proportional risks analysis was used for the multivariate analysis, and the C-statistic was calculated to assess the discriminative power of the models. RESULTS: Hazard ratios (95% CI) estimated for each category of CCI were: 2=1.69 (1.10-2.59), 3=1.78 (1.08-2.92) and 4=1.57 (0.87-2.83) at 30 days; 2=1.62 (1.18-2.23), 3=2.00 (1.39-2.89) and 4=2.24 (1.50-3.36) at 1 year. Comparisons with the C-statistic between the nested multivariate models (with and without CCI) yielded values of 0.765 vs 0.750 after 30 days, and 0.751 vs 0.735 after 1 year. CONCLUSIONS: Our data indicate that CCI is an independent predictor of mortality or recurrent AMI 30 days and 1 year after the index AMI.

Aged↗

Comparison of five typing methods for the epidemiological study of Listeria monocytogenes.

Five typing methods were compared in a study designed to adapt a strategy for epidemiologically typing large numbers of Listeria monocytogenes strains. The methods studied were serotyping, electrophoretic typing of esterases (zymotyping), restriction fragment length polymorphism of ribosomal DNA (ribotyping), random amplified polymorphic DNA (RAPD) and pulsed-field gel electrophoresis (PFGE). Data were analysed by computer-assisted statistical analysis. Included in the analysis were 35 strains of L. monocytogenes, including 14 epidemic strains isolated during outbreaks in France in 1992 and 1993, and 21 strains isolated from food and the environment. Five serotypes, eight zymotypes, ten ribotypes, 13 RAPD patterns and 12 PFGE patterns were identified among the 35 strains. The most discriminating combination of typing methods was ribotyping and PFGE typing [27 types, discriminatory index (D.I.) = 0.978]. A factorial analysis of correspondence for each method differentiated the epidemic strains from the environmental strains. This study shows that computer-assisted statistical treatment of the data, combined with the use of discriminating typing methods, is a powerful tool for the epidemiological analysis of Listeria monocytogenes.

Animals↗

Statistical aspects of bioequivalence--a review.

1. Over the past 20 years a number of statistical methods have been proposed for use in bioequivalence testing. This review examines these methods and reflects current thinking of regulatory authorities. 2. The standard bioequivalence study is conducted as a controlled, single-dose crossover design in a small number of healthy male adults. Blood and/or urine samples are taken at predetermined times for drug/metabolite assay from which pharmacokinetic parameters are derived and compared statistically. Sample size calculations should be determined by the error variance associated with the primary characteristic to be studied, the significance level, the power of the test and the deviation from the reference product compatible with safety and efficacy. 3. In general, bioequivalence is assessed using three parameters namely, Cmax, tmax and AUC. Urinary excretion data may also be used if the amount excreted unchanged is significant. These parameters are best obtained using a simple model-independent approach. 4. The parameters of Cmax and AUC should be logarithmically transformed prior to analysis. For tmax, parametric statistical procedures are not appropriate. 5. Classical hypothesis testing using the power approach is not applicable to the practical problem under consideration in bioequivalence trials. 6. Classical 90% confidence limits and the 2 one-sided t-test approach are operationally identical and are the methods of choice for assessing bioequivalence (Cmax and AUC). When tmax is an important parameter from the clinical point of view then the use of non-parametric confidence intervals is recommended.

Adult↗

Consideration of the challenges, complications, and pitfalls of taxometric analysis.

The taxometric analytic procedures developed by P. E. Meehl and colleagues represent powerful statistical tools for use in the evaluation of observed quantitative data for the possible existence of a qualitative latent class, natural subgroup, or, more commonly, a taxon. Taxometric methods, like any other statistical procedures, require thoughtful application, and the responsibility for proper interpretation of the results from a taxometric study lies with the investigator. Any investigator using taxometric methods must be mindful of those substantive and methodological issues that will facilitate the most fruitful utilization of the general taxometric approach, as well as those issues that will handicap or, perhaps, fatally flaw a taxometric investigation. A number of these issues are highlighted and discussed in this article, and a reader's, writer's, and reviewer's guide for the evaluation of taxometric research reports is provided.

Classification↗

Using multiple imputation for analysis of incomplete data in clinical research.

BACKGROUND: Sample loss and missing data are inevitable in multivariate and longitudinal research. Ad hoc approaches such as analysis of incomplete data or substituting the group mean for missing data, while common, may unnecessarily reduce statistical power and threaten study validity. Multiple imputation for missing data is a newly accessible, methodologically rigorous approach to dealing with the problem of missing data. APPROACH: To (a) discuss the problem of missing data in clinical research, and (b) describe the technique of multiple imputation. A case of analysis of multivariate psychosocial data is presented to illustrate the practice of multiple imputation. RESULTS: The advantages of multiple imputation are it (a) results in unbiased estimates, providing more validity than ad hoc approaches to missing data; (b) uses all available data, preserving sample size and statistical power; (c) may be used with standard statistical software; and, (d) results are readily interpreted. DISCUSSION: Accessible, user-friendly computer programs are available to perform multiple imputation for missing data making ad hoc approaches to missing data obsolete.

Data Interpretation, Statistical↗