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PubMed2005

Two-stage designs for experiments with a large number of hypotheses.

MOTIVATION: When a large number of hypotheses are investigated the false discovery rate (FDR) is commonly applied in gene expression analysis or gene association studies. Conventional single-stage designs may lack power due to low sample sizes for the individual hypotheses. We propose two-stage designs where the first stage is used to screen the 'promising' hypotheses which are further investigated at the second stage with an increased sample size. A multiple test procedure based on sequential individual P-values is proposed to control the FDR for the case of independent normal distributions with known variance. RESULTS: The power of optimal two-stage designs is impressively larger than the power of the corresponding single-stage design with equal costs. Extensions to the case of unknown variances and correlated test statistics are investigated by simulations. Moreover, it is shown that the simple multiple test procedure using first stage data for screening purposes and deriving the test decisions only from second stage data is a very powerful option.

Algorithms↗

PubMed2005

Application of genomewide SNP arrays for detection of simulated susceptibility loci.

The prospect of SNP-based genomewide association analysis has been extensively discussed, but practical experiences remain limited. We performed an association study using a recently developed array of 11,555 SNPs distributed throughout the human genome. A total of 104 DNA samples were hybridized to these chips with an average call rate of 97% (range 85.3-98.6%). The resulting genomewide scans were applied to distinguish between carriers and noncarriers of 37 test variants, used as surrogates for monogenic disease traits. The test variants were not contained in the chip and had been determined by other methods. Without adjustment for multiple testing, the procedure detected 24% of the test variants, but the positive predictive value was low (2%). Adjustment for multiple testing eliminated most false-positive associations, but the share of true positive associations decreased to 10-12%. We also simulated fine-mapping of susceptibility loci by restricting testing to the immediate neighborhood of test variants (+/-5 Mb). This increased the proportion of correctly identified test variants to 22-27%. Simulation of a bigenic inheritance reduced the sensitivity to 1%. Similarly adverse effect had reduction of allelic penetrance. In summary, we demonstrate the feasibility and considerable specificity of SNP array-based association studies to detect variants underlying monogenic, highly penetrant traits. The outcome is affected by allelic frequencies of chip SNPs, by the ratio between simulated "cases" and "controls," and by the degree of linkage disequilibrium. A major improvement is expected from raising the density of the SNP array.

Alleles↗

PubMed1982

Behavioral toxicology in risk assessment: problems and research needs.

Behavioral methods are being used with increasing frequency in toxicology to assess the deleterious effects of chemicals to which we are exposed. The impetus for the use of behavioral techniques in risk assessment resulted from the presumption that they were more sensitive than other tests in detecting toxicity. A more logical reason for the use of behavioral tests is the fact that behavior is the functional indicator of the net sensory, motor, and integrative processes occurring in the central and peripheral nervous system. Thus, the functional capacity of the nervous system cannot be determined independent of behavioral analysis. Some of the problems confronting behavioral toxicology are (1) the translation of human subjective complaints into behavioral tests in animals; (2) determining subtle effects on the nervous system in the face of the well-known functional reserve and adaptability of the system; (3) dealing with the variety of statistical problems resulting from the use of multiple tests, multiple measurements using the same test and the (relatively) large variability inherent in some behavioral phenomena; and (4) selecting the proper tests. Three critical research needs in behavioral toxicology as they relate to risk assessment are (1) development and validation of methods, (2) determining subpopulations at greatest risk, and (3) developing a strategy for determining interactions between two or more agents.

Animals↗

PubMed1996

Full-information models for multiple psychometric tests: annualized rates of change in normal aging and dementia.

The rates of change for five widely used psychometric tests were analyzed to compare how much more variance reduction can be achieved using full-information methods relative to the single-equation methods previously used in dementia research. Nondemented controls and subjects with Alzheimer disease (AD), probable/ possible vascular dementia (VD), or mixed dementia (MD) were evaluated. A cohort design was followed, with follow-up of three demented groups and one normal control group; data were analyzed in a multiple-equation regression model estimated with full-information methods. The study was conducted at Alzheimer's Disease Research Center sites at the University of California, Irvine, and at the University of Southern California. In all, 226 patients and controls who had completed initial assessment and at least one annual reassessment were included in the study. Dependent variables were annualized rates of change in the Mini-Mental State Examination (MMSE), the Short-Blessed Dementia Rating Scale (DRS), the Consortium to Establish a Registry for Alzheimer's Disease drawings test (CD), the WAIS-R Block Design test (WRB), and the Boston Naming Test (BNT). Independent variables were dementia severity, diagnosis (AD, VD, MD, or control), sex, age, marital status, education, and age at onset. Full-information methods reduced the variance in the change scores by > or = 25% compared with previous studies. The model's prediction of a test's rate of change was almost entirely due to dementia stage and diagnosis. The effects of other explanatory variables (sex, marital status, age, and education) were weak and statistically insignificant. When the effects of other independent variables were controlled, AD and MD patients were found to decline at significantly faster rates than VD patients. Full-information methods, relative to single-equation methods, substantially reduce the variance of rates of change for multiple psychometric tests. They do so by simultaneously considering the correlated error terms in the regression for each dependent psychometric change score variable. The robustness of these results to minor variations in follow-up time suggests that annualization is a reasonably valid procedure for making change scores comparable. This study's results suggest that change scores in psychometric tests provide information that can be used to aid differential diagnosis. However, the large variances of change scores preclude many other uses. Finally, since standardization of psychometric change scores translates all tests to the same scale (0-100%), standardized change scores are easier to interpret. The analysis of standardized change scores deserves further investigation.

Age of Onset↗

PubMed1994

Predictive testing for multiple endocrine neoplasia type 2A (MEN 2A) based on the detection of mutations in the RET protooncogene.

BACKGROUND: The identification of inherited mutations in the RET protooncogene (RET) associated with multiple endocrine neoplasia type 2A (MEN 2A) has enabled the development of a genetic test to identify asymptomatic carriers of disease. METHODS: Genomic DNA was extracted from 96 members of an MEN 2A kindred. The polymerase chain reaction was used to amplify the RET exon known to contain the associated mutation. The mutation results in a new restriction endonuclease site and is detected by digestion with the appropriate enzyme. Inheritance of the mutation was verified with a previously developed genetic linkage test. RESULTS: We found that (1) mutations vary among kindreds but are consistently inherited within kindreds, (2) invariable correlation exists between mutation and disease (43 mutations in 43 affected individuals), (3) determination of the genetic status by linkage-based testing was precluded by recombination events and the informativeness of genetic markers, and (4) mutation analysis presymptomatically identified two genetically affected individuals. CONCLUSIONS: Direct genetic analysis for mutations in RET circumvents the limitations of linkage-based genetic testing and current biochemical screening assays. This method will be the diagnostic test of choice for the identification of asymptomatic individuals at risk for MEN 2A.

Amino Acid Sequence↗

PubMed1997

Urinary inhibitors of polymerase chain reaction and ligase chain reaction and testing of multiple specimens may contribute to lower assay sensitivities for diagnosing Chlamydia trachomatis infected women.

In a comparison of commercial ligase chain reaction (LCR; Abbott) and polymerase chain reaction (PCR; Roche) assays, measuring plasmid genes of Chlamydia trachomatis, some specimens were found to be negative by either or both assays but positive in traditional culture or antigen detection tests. Of 767 women, 35 were found to be infected by cervical or urine testing. Twenty three specimens from 16 women may have contained inhibitors in six cervical swabs (CS) and 15 first void urines (FVU). By performing dilution and 'spiking' experiments on five FVU, inhibitors of PCR, LCR or both, which disappeared by dilution, were demonstrated. Confirmatory assays were used which amplified segments of the major outer membrane gene by PCR or LCR. When comparisons of assays were made on a single specimen type, the sensitivities of the amplification assays, compared to an expanded reference standard, were as follows: on CS, PCR was 93.8% (30/32) and LCR was 96.9% (31/32); on FVU, PCR was 76.6% (23/30) and LCR was 93.3% (28/30). When a combined calculation was made to determine the ability of the assays to detect patients infected in the cervix or urethra by testing FVU, the sensitivities dropped to 71.4% (25/35) for PCR and 80.0% (28/35) for LCR: CS sensitivity was 88.6% (31/35) for both amplified tests. There were two CS and five FVU false-positives by PCR which reduced to one CS and three FVU in the combined analysis. There were no false-positives by LCR. Inhibitors and low levels of chlamydial plasmid nucleic acids may have contributed to lower than expected sensitivities, suggesting a possible need for internal positive controls, especially for PCR, when testing urine. More studies with multiple sampling and more than one amplification assay are needed to confirm these findings and to identify and remove inhibitors of amplification assays.

Cervix Uteri↗

PubMed1984

Predictive value of antepartum non-stress test in multiple pregnancies.

Twenty-seven sets of twins in the last trimester of pregnancy underwent 122 antepartum non-stress tests (NST). The NSTs were evaluated by a cardiotocography score. The last test was performed less than one week antepartum. Fifty fetuses had a normal NST, 13 were small-for-gestational age, but only one of these required intensive neonatal care. Four fetuses had one or more pathological NSTs; all 4 were SGA, and these required intensive neonatal care. The pathological variables in the cardiotocograms were reduced variability, absence of spontaneous accelerations, and (late) decelerations. There was no perinatal mortality. Pathological NST was associated with a statistically significantly increased rate of neonatal morbidity, reduced intra-uterine growth and a low one minute Apgar score. For the evaluation of retarded intra-uterine growth, the predictive value of a normal NST was 95.7%, and the predictive value of a pathological NST was 75.0%. The assessment of fetal wellbeing in multiple pregnancy by non-stressed antepartum cardiotocography is of clinical value and seems to be a better predictor of perinatal morbidity than are serial estriol analyses and serial biparietal diameter measurements.

Adult↗

PubMedDate not supplied

[The use of biological markers in the diagnosis and follow-up of patients with multiple sclerosis. Test of five fluids].

PATIENTS AND METHODS: We studied five biological fluids which were easily accessible to immunological examination (cerebrospinal fluid, plasma, tears, saliva and urine) in 25 patients with multiple sclerosis, clinically definite according to the criteria of Cleveland, Ohio (1991) and tabulated according to the Kurztke's expanded disability status scale. The samples were obtained simultaneously during a clinical bout of the disease before any pharmacological or immunosuppressive treatment had been given. RESULTS: The soluble interleukin-2 levels were significantly raised in at least three of these fluids--always absent from the urine--when compared with normal controls. The sensitivity and specificity of this determination for diagnosis of the condition was greater than that of other immunochemical parameters--oligoclonal distribution of immunoglobulins (specifically of IgG), imbalance of the light Kappa and Lambda chains--and physiological studies (evoked potentials). The dosification and quantification of basic myelin protein of the central nervous system, rich in citruline in the urine, may be a parameter of progressiveness. CONCLUSION: This methodology (five humours test) may be used to establish an earlier, more certain diagnosis of multiple sclerosis and also monitor its biological activity together with nuclear magnetic resonance with intravenous contrast.

Adult↗

PubMed2002

Factorial design considerations.

PURPOSE: Factorial designs may be proposed to test extra questions within a clinical trial. A common approach to sample size and analysis for factorial trials assumes no statistical interactions and does not adjust for multiple testing. This investigation considered the trade-off between potential gains from testing more questions with fewer patients versus how often a factorial trial might arrive at an incorrect conclusion. METHODS: A simulation study of a 2 x 2 design (observation v chemotherapy v radiation therapy v the combination) was performed under various conditions, including effect of one, both, or neither treatment and absence or presence of statistical interaction (effect of one treatment differed according to the presence of the other). Three analysis approaches were investigated, one assuming no interaction, a second testing first for interaction, and the third testing for interaction as well as adjusting for multiple testing. The approaches were compared with respect to the probability of selecting the correct treatment arm. RESULTS: No one approach was superior. Testing for interaction was beneficial in some settings but detrimental in others. Under some scenarios, the factorial design improved efficiency, but under others, all three approaches resulted in poor probability of selecting the correct treatment arm at the end of the trial. CONCLUSION: Extra efficiency is possible, but it is difficult to predict when favorable conditions exist. If a factorial design is used, potential efficiency gains should be weighed against potential loss of power to arrive at the correct conclusion under possible scenarios of interest.

Clinical Trials as Topic↗

PubMed2003

[Quality rating of MR-cholangiopancreatography with oral application of iron oxide particles].

PURPOSE: To compare image quality in magnetic resonance cholangiopancreatography (MRCP) performed with and without oral application of Lösferron (ferrous gluconate, Lilly Pharma, Hamburg). MATERIALS AND METHODS: A prospective study compares MRCPs performed on 52 patients with a 1.5 T clinical whole body scanner using a standard body coil. After randomization, patients ingested either 0.5 l of Lösferron (n = 27, group 1) or no oral contrast agent (n = 25, group 2) prior to the examination. 7 RARE (40 to 20 degrees) sequences were obtained, followed by selected 3 mm HASTE (T 2 -weighted with fat suppression) sequences. After blinding, image quality was rated by two radiologists using a scale of 1 (not discernible) to 5 (very well discernible). The following sections of the biliary ductal system were evaluated: left and right hepatic duct, extrahepatic bile duct and intrapancreatic bile duct. The pancreatic duct was evaluated by its location: head, body and tail of the pancreas. A Wilcoxon-Mann-Whitney test was used to determine significant differences (p < 0.05) between sampled ductal segments. Correction for multiple testing was applied. RESULTS: The oral application of Lösferron was well tolerated by all patients, and all sequences could be acquired and evaluated in all 52 patients. For the different sections of the biliary system, the mean ratings with and without Lösferron were, respectively, 3.28 and 3.36 for the left hepatic duct, 3.26 and 3.33 for the right hepatic duct, 3.46 and 4.0 for the extrahepatic bile duct, and 2.8 and 3.48 for the intrapancreatic bile duct. The corresponding ratings for the pancreatic duct were 2.8 and 3.24 for the pancreatic head, 2.84 and 3.38 for the pancreatic body, and 2.68 and 3.22 for the pancreatic tail. The differences with and without contrast agent were not statistically significant. Interobserver variability was between 0.37 for the pancreatic duct in the tail of the pancreas and 0.66 for the right hepatic duct. CONCLUSION: Despite the trend toward a better rating of the image quality for all sections of the pancreaticobiliary ductal system with Lösferron, a significant difference was not found in any ductal section after correction for multiple testing. Thus, we believe that the ingestion of Lösferron is not absolutely required prior MRCP.

Administration, Oral↗

PubMedDate not supplied

A stochastic downhill search algorithm for estimating the local false discovery rate.

Screening for differential gene expression in microarray studies leads to difficult large-scale multiple testing problems. The local false discovery rate is a statistical concept for quantifying uncertainty in multiple testing. In this paper, we introduce a novel estimator for the local false discovery rate that is based on an algorithm which splits all genes into two groups, representing induced and noninduced genes, respectively. Starting from the full set of genes, we successively exclude genes until the gene-wise p-values of the remaining genes look like a typical sample from a uniform distribution. In comparison to other methods, our algorithm performs compatibly in detecting the shape of the local false discovery rate and has a smaller bias with respect to estimating the overall percentage of noninduced genes. Our algorithm is implemented in the Bioconductor compatible R package TWILIGHT version 1.0.1, which is available from http://compdiag.molgen.mpg.de/software or from the Bioconductor project at http://www.bioconductor.org.

Algorithms↗

PubMed2005

Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach.

The most commonly used method in evolutionary biology for combining information across multiple tests of the same null hypothesis is Fisher's combined probability test. This note shows that an alternative method called the weighted Z-test has more power and more precision than does Fisher's test. Furthermore, in contrast to some statements in the literature, the weighted Z-method is superior to the unweighted Z-transform approach. The results in this note show that, when combining P-values from multiple tests of the same hypothesis, the weighted Z-method should be preferred.

Biological Evolution↗

PubMed1992

Multiple equivalent test forms in a computerized, everyday memory battery.

Eight parallel forms for six computerized, everyday memory tests were examined for equivalence of difficulty level. Six equivalent forms were found for Telephone Dialing, Name-Face Association, First-Last Name memory, and Grocery List Learning, white eight equivalent forms were found for Misplaced Objects and Recognition of Faces. The clinical and research utility of multiple equivalent forms of everyday memory tests is discussed.

Journal Article↗

PubMed1980

Assessing laboratory evidence for neoplastic activity.

A variety of statistical issues which arise in the analysis of tumorigenesis assay data are reviewed. Tumor acceleration appeared as a possibility in the Red Dye 40 situation and that phenomenon is discussed. Experimental design considerations covered include sex, cage locations, and whether there is complete randomization, or whether littermates are stratified across doses, or whether, as in multigeneration studies, all littermates are treated alike. Whichever, the statistical analysis should be appropriate. Statistical techniques must take into account the time-to-response aspect in the detection of palpable tumors along with the complication of censored observation due to interim mortality. A logrank technique for accomplishing this must be further adjusted so as to handle tumors detectable only on necropsy. Dosage effects may be sought in a variety of ways, including alternative procedures for identifying progressive dosage effects. Separate analyses may be conducted for separate tumor sites or types, introducing a multiple-testing aspect. Because of the sparseness of data for many individual tumor sites, the usual multiple-testing procedures have to be modified. Statistical analysis, however, is only a guide to the careful interpretation of results, and the need to take action as a result of that interpretation remains.

Animals↗

PubMed1985

The flight of colors test in multiple sclerosis.

Flight of colors (FOC), the rapidly changing series of colored afterimages perceived when a bright light briefly strikes the eye, is impaired or absent in patients with lesions affecting central visual fields, especially optic neuropathies (ONs). The effectiveness of a bedside test of FOC using a pocket flashlight was compared with that of pattern-reversal visual evoked responses (PRVERs) in examining 74 subjects): 20 controls, seven patients with ON not due to multiple sclerosis (MS), 26 patients with MS, and 21 patients with possible MS and no clinical ON. The FOC test correctly identified 95 of 99 normal eyes and 45 of 49 eyes with ON, and accurately diagnosed 140 (95%) of 148 eyes overall. In 84 eyes examined by PRVER and FOC, the results agreed in 73 cases (87%), including those of subclinical ON.

Adult↗

PubMed1985

[Otoneurologic testing in multiple sclerosis].

The values of the individual audiological and vestibular examination methods in multiple sclerosis (MS) diagnosis are discussed. Our experience shows that the most accurate indications are provided by acoustic stapedius reflex, brainstem auditory evoked potentials (BAEPs) and vestibular investigation. Other testing processes play only a minor part. Using the three methods mentioned, brainstem injuries can be shown to be present at an early stage. Hence one should always include them in MS-diagnosis as a matter of routine. Of the 85 patients we examined, 72 had definite MS and 13 probable (sub-division according to Mc Alpine criteria): all of them underwent acoustic stapedius reflex test and vestibular investigation (nystagmogram, caloric vestibular test according to Hallpike-Frenzel. The stapedius reflex measurements showed pathological findings of 64/54% and the vestibular test findings of 53/61%.

Adult↗

PubMed1998

Cuing effect of "all of the above" on the reliability and validity of multiple-choice test items.

It is generally acknowledged that alternatives such as none of the above and all of the above should be used sparingly in multiple-choice (MC) items. But the effect that all of the above has on the reliability and validity of an MC item is unclear. This study compared the results of a single-response (SRa) item format that included all of the above as the correct response to a multiple-response (MR) item format that required examinees to select all of the available alternatives for a correct response. A crossover design was used to compare the effect of formats on student performance while item content, scoring method, and student ability levels remained constant. Results indicated that the SRa format greatly distorted examinee performance by elevating their scores because examinees who recognized two or more alternatives as being correct were cued to select all of the above. In addition, the SRa format significantly reduced the reliability and concurrent validity of examinee scores. In summary, the MR format was found to be superior. Based upon new empirical evidence, this study recommends that whenever an educator wishes to evaluate student understanding of an issue that has multiple facts, the SRa format should be avoided and the MR format should be used instead.

Alberta↗

PubMed2005

Counterregulatory eating behavior in multiple item test meals.

Restrained eaters have been shown to disinhibit their eating when under stressful situations. However, the majority of laboratory studies that have demonstrated this effect utilized a single test food, typically ice cream. There is a lack of research investigating if this interaction is still evident when multiple foods are offered, and if so, the food choices that restrained and non-restrained eaters make when under stressful situations. The present study examined the impact of stress on food choices in individuals with varying degrees of restraint. Several classes of foods were offered (i.e., high fat/high sugar; low fat/high sugar; high fat/low sugar; low fat/low sugar). A total of 153 females were randomly assigned to either a stress or no-stress situation, and then both groups participated in a taste test. There was no significant difference in total amount of consumption between restrained and non-restrained eaters when under stress. However, further analyses found that restrained eaters under stress consumed more potato chips than those who were not under stress. Findings are discussed in terms of possible limitations of the stress-induced eating paradigm for restrained eaters.

Adult↗