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PubMed2006

Resampling-based multiple hypothesis testing procedures for genetic case-control association studies.

In case-control studies of unrelated subjects, gene-based hypothesis tests consider whether any tested feature in a candidate gene--single nucleotide polymorphisms (SNPs), haplotypes, or both--are associated with disease. Standard statistical tests are available that control the false-positive rate at the nominal level over all polymorphisms considered. However, more powerful tests can be constructed that use permutation resampling to account for correlations between polymorphisms and test statistics. A key question is whether the gain in power is large enough to justify the computational burden. We compared the computationally simple Simes Global Test to the min P test, which considers the permutation distribution of the minimum p-value from marginal tests of each SNP. In simulation studies incorporating empirical haplotype structures in 15 genes, the min P test controlled the type I error, and was modestly more powerful than the Simes test, by 2.1 percentage points on average. When disease susceptibility was conferred by a haplotype, the min P test sometimes, but not always, under-performed haplotype analysis. A resampling-based omnibus test combining the min P and haplotype frequency test controlled the type I error, and closely tracked the more powerful of the two component tests. This test achieved consistent gains in power (5.7 percentage points on average), compared to a simple Bonferroni test of Simes and haplotype analysis. Using data from the Shanghai Biliary Tract Cancer Study, the advantages of the newly proposed omnibus test were apparent in a population-based study of bile duct cancer and polymorphisms in the prostaglandin-endoperoxide synthase 2 (PTGS2) gene.

Algorithms↗
PubMed1988

Identifying important results from multiple statistical tests.

When many statistical tests are performed simultaneously, the overall chance of a type I error (incorrect rejection of a true null hypothesis) can substantially exceed the nominal error rate used in each individual test. Numerous techniques exist to adjust results of individual tests to control this problem. In general, these techniques apply a more stringent criterion of statistical significance (a smaller P-value) to each individual test than normally needed to maintain the experimentwise type I error. With an analysis that seeks to identify results for further research, however, such a conservative technique may not be appropriate. We present a new approach that uses a mixture of several distributions to model the set of P-values or of test statistics. One component models the results consistent with a failure to reject the null hypothesis, while the other distribution(s) in the mixture represent results inconsistent with the null hypothesis. These latter results may not achieve statistical significance based on a conventional P-value. We illustrate the use of the method on national mortality data and on several data sets analysed previously.

Cause of Death↗
PubMed1995

Improved carrier testing for multiple endocrine neoplasia, type 1, using new microsatellite-type DNA markers.

Familial multiple endocrine neoplasia, type 1 (FMEN1), is an autosomal dominant trait generated by hyperfunction of various endocrine glands. The gene for MEN1 has been mapped to chromosome 11q13 by genetic linkage and deletion mapping in tumors. Eight Finnish families, including 46 individuals carrying the risk haplotype, have been typed for four polymorphic microsatellite DNA markers spanning the MEN1 chromosomal region. Three of the loci concerned, D11S913, D11S987, and D11S1337, displayed maximum lod scores (Zmax) 6.70, 9.88, and 2.54, respectively, with no recombinations with the disease gene, whereas a Zmax of 8.43 was obtained for D11S971 at a recombination fraction of 0.03. Our results indicate that the use of this set of markers considerably improves the diagnostic value of genotyping patients at risk of developing MEN1.

Alleles↗
PubMed2004

A test of multiple hypotheses for the species richness gradient of South American owls.

Many mechanisms have been proposed to explain broad scale spatial patterns in species richness. In this paper, we evaluate five explanations for geographic gradients in species richness, using South American owls as a model. We compared the explanatory power of contemporary climate, landcover diversity, spatial climatic heterogeneity, evolutionary history, and area. An important aspect of our analyses is that very different hypotheses, such as history and area, can be quantified at the same observation scale and, consequently can be incorporated into a single analytical framework. Both area effects and owl phylogenetic history were poorly associated with richness, whereas contemporary climate, climatic heterogeneity at the mesoscale and landcover diversity explained ca. 53% of the variation in species richness. We conclude that both climate and environmental heterogeneity should be retained as plausible explanations for the diversity gradient. Turnover rates and scaling effects, on the other hand, although perhaps useful for detecting faunal changes and beta diversity at local and regional scales, are not strong explanations for the owl diversity gradient.

Animals↗
PubMed2005

Contributions of marginal offspring to reproductive success of Nazca booby (Sula granti) parents: tests of multiple hypotheses.

While obligate siblicide is a phylogenetically widespread behavior, known from plants, insects, birds, and other taxa, with important implications for life history evolution, comprehensive evaluations of its costs and benefits to parents are rare. We used 12 years of breeding and band resight data to evaluate the importance of several potential benefits that marginal offspring (the usual victims of obligate siblicide) could provide to parent Nazca boobies (Sula granti), a seabird. We found no evidence for the resource-tracking hypothesis: 99.95% of two-chick broods were reduced to one chick before fledging, and the single exceptional brood probably lost one chick between fledging and independence. Behavioral observations indicated that siblicidal aggression caused most mortality of marginal chicks, and at least contributed to the remainder. We also found no evidence that marginal offspring provide a food resource for other family members. Marginal chicks benefit parents via adoption into other families, and possibly also in the context of progeny choice, but these benefits are minor compared to the insurance that marginal chicks provide against early failure of core (first-hatched) offspring. Further evaluation of the Insurance Egg Hypothesis showed that marginal and core offspring are functionally equivalent in the absence of sibling interactions, and that core offspring incur no detectable costs from behaving siblicidally. Nazca boobies are truly obligate brood reducers, with parents receiving principally insurance benefits from marginal offspring, but many birds and other taxa exhibiting persistent, unconditional sibling aggression do not exhibit universal brood reduction. Insurance is only one of several potential benefits that marginal offspring can confer on parents, and a multi-hypothesis approach to decompose the different types of benefits is required to understand the evolution of clutch size in other obligately siblicidal species.

Animals↗
PubMed2005

CNS involvement occurs more frequently in patients with Behçet's disease under cyclosporin A (CSA) than under other medications--results of a retrospective analysis of 117 cases.

The aim of this study was to evaluate the incidence of neurological manifestations of Behçet's disease (BD) in patients on cyclosporin A (CSA) compared with those on other medications. The records of 117 patients with BD who visited our hospital between 1990 and 2003 were reviewed with respect to symptoms and medication. All episodes of constant therapy prior to central nervous system (CNS) involvement were counted, and then the associations were analysed by the exact Fisher-Freeman-Halton test and adjusted for multiple tests by the Bonferroni-Holm method. We observed ten new cases of CNS manifestations in our patients with BD being regularly seen and treated in our tertiary care centre. The overall prevalence of neuro-BD in our patient group was 8.5%. In a retrospective analysis, the incidence of new-onset neurological disease (neuro-BD) in all patients with BD who regularly visited our hospital was significantly higher in patients on CSA than in those on other medications (6 of 21 vs 0 of 175 episodes, P<0.0001). This contrasts the obvious efficacy of CSA on extracerebral manifestations of BD, such as severe ocular disease, mucocutaneous lesions or arthritis. CSA exerts differential efficacy on various manifestations of BD. It is very effective for severe ocular and other moderate to severe manifestations of BD, but its efficacy for the prevention of neuro-BD seems to be inferior to that of other medications used in BD, such as azathioprine or interferon-alpha. The reasons for this are unclear, but the potential toxic effects of CSA on the CNS may be a predisposing factor for CNS vasculitis in BD.

Adolescent↗
PubMed1989

Simultaneous use of multiple serologic tests in assessing clinical activity in systemic lupus erythematosus.

Ten technics for quantifying and qualifying anti-DNA antibodies were correlated with manifestations of disease activity in sera from 27 patients with systemic lupus erythematosus (SLE) using both a simple and a stepwise regression. In the stepwise analysis, a panel consisting of four of these tests provided maximal correlation (r = 0.68) with clinical status. Low IgM anti-DNA was a significant correlate of nephritis in stepwise discriminant function analysis. Multivariate analysis can offer distinct advantages over simple correlation in understanding the role of serological abnormalities in disease expression in SLE.

Autoantibodies↗
PubMed2004

Mice lacking leukocyte common antigen-related (LAR) protein tyrosine phosphatase domains demonstrate spatial learning impairment in the two-trial water maze and hyperactivity in multiple behavioural tests.

Leukocyte common antigen-related (LAR) protein is a cell adhesion molecule-like receptor-type protein tyrosine phosphatase. We previously reported that in LAR tyrosine phosphatase-deficient (LAR-Delta P) mice the number and size of basal forebrain cholinergic neurons as well as their innervation of the hippocampal area was reduced. With the hippocampus being implicated in behavioural activity aspects, including learning and memory processes, we assessed possible phenotypic consequences of LAR phosphatase deficiency using a battery of rodent behaviour tests. Motor function and co-ordination tests as well as spatial learning ability assays did not reveal any performance differences between wildtype and LAR-Delta P mice. A spatial learning impairment was found in the difficult variant of the Morris water maze. Exploration, nestbuilding and activity tests indicated that LAR-Delta P mice were more active than wildtype littermates. The observed hyperactivity in LAR-Delta P mice could not be explained by altered anxiety or curiosity levels, and was found to be persistent throughout the nocturnal period. In conclusion, behavioural testing of the LAR-Delta P mice revealed a spatial learning impairment and a significant increase in activity.

Animals↗
PubMed2006

Design and in vitro performance testing of multiple air classifier technology in a new disposable inhaler concept (Twincer) for high powder doses.

Dry powder inhalation of antibiotics in cystic fibrosis (CF) therapy may be a valuable alternative for wet nebulisation, because it saves time and it improves lung deposition. In this study, it is shown that the use of multiple air classifier technology enables effective dispersion of large amounts of micronised powder (up to 25mg). X(50)-values of the aerosol from laser diffraction analysis obtained with the Twincer disposable inhaler concept (containing multiple air classifier technology) are practically the same as that for the pure drug in the range of dose weights between 0 and 25mg. Only for the highest dose weights, a minor fraction (5-7.5%) of small agglomerates (5-15microm) is released from the inhaler. Moreover, the size distribution of the aerosol is practically the same at 1 and 4kPa. Cascade impactor results confirm the good performance of the multiple classifier concept. Unprocessed micronised particles or soft spherical agglomerates can be used, and special particle engineering processes are not necessary. Only a minor fraction of coarse sweeper crystals in the formulation is desired to reduce the total inhaler losses for colistin sulfomethate to less than 5-6% at 4kPa. The classifiers can be designed to retain these crystals with more than 95% efficiency.

Administration, Inhalation↗
PubMed2001

Mitigation of the clinical significance of spurious elevations of cardiac troponin I in settings of coronary ischemia using serial testing of multiple cardiac markers.

The ability to differentiate between true positives, false positives, and sporadically elevated cardiac troponin levels has grown in importance as cardiac troponins assume an increasingly dominant role in the diagnosis of coronary syndromes. In a population sample of 1,000 patients who presented consecutively to a large urban hospital emergency room, 50 of 112 patients who had elevated troponin levels (> 0.6 ng/ml) during evaluation for myocardial injury were subsequently found to have had an isolated, spurious elevation of cardiac troponin, and not a diagnosed myocardial infarction. Logistic regression analysis shows that by hierarchically analyzing electrocardiographic changes with concurrent creating kinase-MB and myoglobin levels at the time of the troponin elevation, one may predict with 91% accuracy whether the troponin elevation is actually indicative of a myocardial infarction in a patient. Spurious troponin elevations may be a common occurrence, and if not detected, may result in an increased number of falsely diagnosed myocardial infarctions.

Aged↗
PubMed1979

A simple and sensitive nonradioactive method for the detection of urinary human chorionic gonadotropin and diagnosis of early human pregnancy. I. Multiple-unit test.

A simple, sensitive, and reproducible method for the detection of urinary human chorionic gonadotropin (hCG) and diagnosis of early human pregnancy is reported. A 5-ml aliquot of filtered early-morning urine sample was concentrated in a microconcentrator (M) to 0.1 ml of retentate which was diluted with 0.4 ml of distilled water and tested in a hemagglutination inhibition test (M-HIT). Also, a 0.1-ml aliquot of filtered unconcentrated urine sample was diluted with 0.4 ml of distilled water and tested in the same hemagglutination inhibition test (HIT). Urine samples from women of reproductive age; from perimenopausal, menopausal, and proteinuric women; and from adult males were tested in the HIT and M-HIT. Some of these urine samples were also tested in the mouse ovulation bioassay (MOB). The M-HIT was significantly more reliable than the HIT for diagnosis of early pregnancy 25 to 55 days after menses. Correct negative results with the M-HIT were obtained in urine samples of most of the nonpregnant cycling, perimenopausal, and menopausal women, and adult males. Urine samples from subjects with severe proteinuria gave false-positive types of reactions in the M-HIT. Positive results were obtained in the MOB with a number of urine samples from pregnant, perimenopausal, and menopausal women. A properly conducted M-HIT should be very valuable in diagnosing pregnancy as early as the 26th day of the cycle in regularly menstruating women.

Chorionic Gonadotropin↗
PubMed1998

Longitudinal follow-up of cardiovascular reflex tests in multiple sclerosis.

Several studies have shown various degrees of autonomic dysfunction in patients with multiple sclerosis. Longitudinal follow-up studies are remarkably scarce up to now. We assessed autonomic dysfunction twice with an interval of 1 year in 20 relapsing remitting and 26 secondary progressive MS-patients. Autonomic function was assessed by the heart rate response during deep breathing, standing up and Valsalva manoeuvre. Only the maximum change in heart rate after standing up (in ms and beats/min) and the Max/Min ratio after standing up showed significant worsening over 1 year. The changes in EDSS scores also documented gradual deterioration of the neurological condition over the study period. We conclude that there is progression of autonomic dysfunction in MS over 1 year and that this could correlate with progression in clinical disability.

Adult↗