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PubMed1999

The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits.

The statistical power of five association study test statistics (two haplotype-based tests, two marker-based tests, and the Transmission Disequilibrium Test-Q5) to detect single nucleotide polymorphism (SNP)/phenotype associations in a linkage-disequilibrium-based candidate gene scan employing a number of SNPs is examined. Power is estimated as a function of realistic parameters expected to affect the likelihood of detecting a significant association: the number of SNPs examined, the scaled recombination size of the region examined, the proportion of variance in the trait attributable to a hidden causative polymorphism within the region, and the number of individuals or families examined. For the different combinations of parameter values, power is estimated from a large number of realizations of a simulated coalescent describing a single random mating population with mutation, random genetic drift, and recombination. This explicit population genetics model results in a distribution of DNA marker heterozygosities and linkage disequilibria that are likely to resemble those expected in actual population samples. The study concludes that (1) marker-based permutation tests are more powerful than simple haplotype-based tests, (2) there is sufficient power to detect the presence of causative polymorphisms of small effect if on the order of 500 individuals are sampled, (3) greater power is achieved by increasing the sample size than by increasing the number of polymorphisms, (4) association studies are generally more powerful than transmission disequilibrium-based tests, and (5) for the range of parameters considered association studies have a low repeatability unless sample sizes are on the order of 500 individuals. Estimates of 4Nc for a number of gene regions and human populations will be of use in determining the density of SNPs that are likely to be required for successful association studies.

Computational Biology↗
PubMed1994

Comparison of the EMG power spectrum of the human soleus and gastrocnemius muscles.

The purpose of this study was to compare the behaviour of electromyographic (EMG) power spectrum statistics, mean power frequency (MPF) and median frequency (MF), across increasing force levels of the soleus (SO), gastrocnemius medialis (GM) and gastrocnemius lateralis (GL) muscles. Surface EMG signals of these three muscles were recorded in 12 men and 10 women during both (1) ramp (single ongoing contractions with the force increasing linearly from 0 to 100% of the maximum voluntary contraction (MVC); and (2) step (steady force levels: 10, 20, 30, 40, 60 and 80% MVC) static (isometric) plantar flexions. Power spectral analysis of these signals was performed on single 256-ms windows at all of the above-mentioned force levels, for both types of contraction. The MF and MPF were calculated from each of the obtained spectra. A less pronounced increase in the MF or MPF was expected for the SO because of its higher type I fibre content. The main results are as follows: (1) similar behaviours were found in the value of MPF and MF across increasing force for the SO and GL muscles, while the GM gave rise to a different behaviour; (2) no difference was found between ramp and step contractions in the behaviour of either MF or MPF across force levels; and (3) different behaviours were observed between the MF and MPF across increasing force levels, for both ramp and step contractions. Our initial expectations were thus not confirmed. It is concluded that the present results support the hypothesis that the EMG power spectrum may be more sensitive to the diameter of the fibres than to the fibre type proportion of the triceps surae muscles. Furthermore, the sensitivity of the power spectrum statistics of a given muscle to the low-pass filter effect of its skin layer was also emphasized.

Adult↗
PubMed2006

Insular infarcts and electrocardiographic changes at admission: results of the PRognostic of Insular CErebral infarctS Study (PRINCESS).

BACKGROUND AND PURPOSE: Previous studies showed that insular strokes are associated with electrocardiographic (ECG) changes. However, they did not take into account the 1(st) ECG recorded at admission, but continuous ECG recorded up to 72 hours after onset. Whether these changes are the consequence of the infarct, or are associated with a cardiac source of cerebral ischemia, remains unsettled. If ECG changes are the consequence of insular infarcts, they should not have developed by the time of admission. The aim of this study was to test the hypothesis that ECG changes in patients with insular infarcts are not present at admission. METHODS: We recruited consecutive patients admitted within 48 hours (median 3 hours) after the onset of symptoms of acute hemispheric cerebral ischemia. We compared ECG variables between patients with and without insular infarcts, and with left and right insular infarcts. RESULTS: The study population consisted of 208 patients (94 men; median age: 69 years). Seventy patients had a recent insular infarct (right in 33). ECG variables did not significantly differ between patients with and without insular infarcts, and with left and right insular infarcts. These results were not explained by a lack of statistical power (1-beta >/= 0.90). CONCLUSION: The lack of statistical link between insular infarcts and ECG changes at admission, suggests that ECG changes are not associated with the cause of insular infarcts, but are their consequence.

Adolescent↗
PubMed1996

Testing the indeterminacy of linear color mechanisms from color discrimination data.

It have previously been reported that, for some choices of the fixed spatial and temporal characteristics of test stimuli, it was possible to estimate the spectral sensitivities of chromatic mechanisms from chromatic discrimination data alone. If mechanism sensitivities could be reliably estimated for any choice of test stimuli characteristics, the influence of spatial and temporal factors on chromatic discrimination performance could be directly measured. Previous studies, using test stimuli with other spatio-temporal characteristics, have found equi-discrimination contours whose ellipsoidal shapes seem to preclude estimation of mechanisms. Since there is no commonly-accepted method for testing the adequacy of ellipsoidal fits of chromatic equi-discrimination contours, it is possible that alternative psychophysical procedures combined with more powerful statistical tests could detect the pattern of deviations from ellipticality reported previously. In this paper, we described psychophysical tests and statistical analyses that, taken together, provide a more powerful test of the indeterminacy of mechanisms than previous methods. We develop a method based on analysis of residuals for detecting the pattern of deviations from ellipticality. We apply these tests under fixed experimental conditions similar to those in which other researchers have found ellipsoidal equi-discrimination contours. For these conditions, for any of the tests performed, we do not reject the hypothesis that equi-discrimination surfaces are ellipsoidal.

Color Perception↗
PubMed2004

Low Dose Rate Irradiation Facility: initial study on chronic exposures to medaka.

Uncertainties associated with the effects from chronic low-level exposures to radiation prompted us to construct a Low Dose Rate Irradiation Facility (LoDIF). The facility was designed specifically to test the appropriateness of the 10 mGy d(-1) guideline often espoused as acceptable for protection of aquatic biota from ionizing radiation. Scientists at the 0.4 ha facility use 40 outdoor mesocosms and 137Cs irradiators of three different source strengths to research the effects of chronic low-level irradiation at different levels of biological organization. A description of the facility is included along with results from a pilot study in which Japanese medaka (a small fish native to Asia) were chronically irradiated at the highest dose rate possible within the facility (350+/-150 mGy d(-1)). Irradiated fish produced fewer eggs per day (p=0.03); had a lower percentage of viable eggs (p=0.04), and produced a lower percentage of hatchlings (p=0.05). Although these data are not surprising based on the relatively high dose rates, they are important to future work at the LoDIF because they confirm the utility of our chosen model organism for detecting population-level responses, and they illustrate the statistical power achieved from using replicated mesocosms, in that statistical significance was achieved with few replicates per treatment. Future directions for the LoDIF are presented, as well as an invitation for interested researchers to participate in our studies.

Animals↗
PubMed1997

Comparing predictors of willingness to treat HIV+ patients for New York City male and female general practice dentists 50 years of age or younger.

OBJECTIVES: This article develops and compares gender-specific predictive models for willingness to treat HIV-infected patients (PHIV+) for male and female private general practice dentists (GPDs). METHODS: Based on mail survey data collected in Manhattan and Queens, New York City (73.3% response rate), hierarchical multiple regression analyses were conducted for male and female dentists 50 years of age or younger (n = 763) and for those in solo practice. RESULTS: The gender-specific predictive models (R2s = 0.72) do not differ, except for the influence of practice viability, a moderately strong, statistically significant predictor for men, while the least powerful, statistically nonsignificant predictor for women. This distinction remains for solo male and female practitioners. Informal/formal collegial norms are more influential predictors within the solo female model than within the solo male model. CONCLUSIONS: Findings are encouraging for further work in developing predictive models for clinician subpopulations, with an eye toward developing intervention strategies that reflect key predictive factors for each group.

Acquired Immunodeficiency Syndrome↗
PubMed2004

[An educational training program for physicians for diagnosis and treatment of depression].

OBJECTIVE: The American Regional Office of the WHO has launched a major initiative to reduce the prevalence of affective disorders region-wide that includes focusing on the primary health care system. This study evaluated the results of an educational training program for Brazilian primary care physicians that measured changes in knowledge, attitudes, and practice. METHODS: A total of 17 primary care physicians and 1,224 patients participated in the study. Physician's knowledge, attitudes, and clinical practice were assessed one-month prior and one-month following the training program. In addition, the patients that visited the clinic during a typical week completed depression symptom self-ratings, including the Zung and a DSM-IV/ICD-10 major depression checklist at both times. RESULTS: The training program showed limited benefits in this small sample of physicians. The program was unable to demonstrate benefit in improving knowledge about depression and in changing disorder-related attitudes. There were no changes in the diagnostic rates of major depression. There was some evidence to support improvement in psychopharmacological management. The physicians seemed more confident in treating patients, as there was a reduction of referrals to the specialists. Lack of statistical power prevented the latter two findings from reaching statistical significance. CONCLUSIONS: The inclusion of primary care physicians is a central component of any initiative to reduce the treatment gap and lag of depression. However, more effective methods of training Brazilian primary care physicians in the management of major depression need to be tested.

Chi-Square Distribution↗
PubMedDate not supplied

Cold stress, reverse T3 and lymphocyte function.

Following a recently reported rise in serum reverse triiodothyronine levels in response to cold exposure, an initial in vitro study has been carried out on human lymphocyte function. The first part of the study demonstrated that the uptake of rT3 on lymphocyte nuclear receptors increased as the rT3 concentration was raised above the normal serum level. The binding is competitive with triiodothyronine. The lymphocytes were harvested from venous blood donated by young male U.S. naval personnel. The second part of the study involved lymphocyte proliferation assays carried out with the addition of increasing amounts of rT3. Both non-specific (three different mitogens) and specific (recall antigen) stimuli were used. There was an indication that lymphocyte function is depressed by increasing serum concentration of rT3. However, with a small number of test subjects and a resulting low statistical power, it was not possible to establish a statistically significant association. Lymphocytes from umbilical cord blood, which has a very high level of rT3 compared to that in normal adult sera, were also found to have a much reduced lymphocyte stimulation index. The requirements for a more definitive investigation are outlined.

Adult↗
PubMedDate not supplied

Increasing the power of clinical trials through judgment analysis.

A method for increasing the statistical power of clinical trials to detect clinically important differences is described. Inconsistency in physicians' overall judgments of treatment effectiveness adds "noise" to a trial that may mask either the superiority or the inferiority of particular treatments. The method described here uses "judgment analysis" to reduce errors in an individual's overall judgments of treatment effectiveness. The method can also be used to reduce error variance due to differences in judgment between physicians and may thus be particularly useful in multicenter trials. The method is illustrated with results from a recent trial.

Analgesics↗
PubMed1994

The statistical analysis of slope ratio assays using SAS software.

SAS is a powerful statistical package but it does not cover all analyses that a user may require particularly in a specialized area such as biological assay. A SAS program SLOPE has been developed for the analysis of biological assays in complete randomization based on the slope ratio method. The program is capable of checking the statistical validity of an assay and estimating the potencies of test preparations relative to a standard. It calculates potencies and their corresponding confidence intervals for a group of bioassays where each assay has equal number of preparations. It also allows the user to produce scatter plots of response by dose.

Analysis of Variance↗
PubMed1998

Type II (beta) errors in the hand literature: the importance of power.

When a study concludes that there is no difference between 2 treatments ("negative studies"), it is essential to determine whether the study has sufficient power to find a clinically significant difference. Insufficient power precludes an adequate assessment of therapeutic efficacy and may result in a type II error, an erroneous conclusion that the null hypothesis is correct. In evaluating 39 studies that highlighted negative findings in The Journal of Hand Surgery, we found that 32 (82%) papers had a power of less than .80 to detect a 25% treatment effect and, when the treatment effect was increased to 50%, more than one half of the studies still had a power of 0.80. These "negative studies" frequently have inadequate statistical power to support their conclusions. These findings have important implications for researchers, editors, and readers.

Animals↗
PubMed2002

Multipoint linkage detection in the presence of heterogeneity.

Linkage heterogeneity is common for complex diseases. It is well known that loss of statistical power for detecting linkage will result if one assumes complete homogeneity in the presence of linkage heterogeneity. To this end, Smith (1963, Annals of Human Genetics 27, 175-182) proposed an admixture model to account for linkage heterogeneity. It is well known that for this model, the conventional chi-squared approximation to the likelihood ratio test for no linkage does not apply even when the sample size is large. By dealing with nuclear families and one marker at a time for genetic diseases with simple modes of inheritance, score-based test statistics (Liang and Rathouz, 1999, Biometrics 55, 65-74) and likelihood-ratio-based test statistics (Lemdani and Pons, 1995, Biometrics 51, 1033-1041) have been proposed which have a simple large-sample distribution under the null hypothesis of linkage. In this paper, we extend their work to more practical situations that include information from multiple markers and multi-generational pedigrees while allowing for a class of general genetic models. Three different approaches are proposed to eliminate the nuisance parameters in these test statistics. We show that all three approaches lead to the same asymptotic distribution under the null hypothesis of no linkage. Simulation results show that the proposed test statistics have adequate power to detect linkage and that the performances of these two classes of test statistics are quite comparable. We have applied the proposed method to a family study of asthma (Barnes et al., 1996), in which the score-based test shows evidence of linkage with p-value <0.0001 in the region of interest on chromosome 12. Additionally, we have implemented this score-based test within the frequently used computer package GENEHUNTER.

Journal Article↗
PubMed2000

Statistical methods for detecting molecular adaptation.

The past few years have seen the development of powerful statistical methods for detecting adaptive molecular evolution. These methods compare synonymous and nonsynonymous substitution rates in protein-coding genes, and regard a nonsynonymous rate elevated above the synonymous rate as evidence for darwinian selection. Numerous cases of molecular adaptation are being identified in various systems from viruses to humans. Although previous analyses averaging rates over sites and time have little power, recent methods designed to detect positive selection at individual sites and lineages have been successful. Here, we summarize recent statistical methods for detecting molecular adaptation, and discuss their limitations and possible improvements.

Journal Article↗
PubMed2003

Common variant in betaine-homocysteine methyltransferase (BHMT) and risk for spina bifida.

Neural tube defects (NTD) are common malformations resulting from incomplete closure of the neural tube in the first month after conception. Since genetic deficiencies in folate-dependent homocysteine metabolism have been identified in NTD families, we investigated a common variant in betaine-homocysteine methyltransferase (BHMT), 742G-->A (R239Q), as a genetic modifier of NTD risk. Genotypes, nutrient levels, and plasma total homocysteine (tHcy) were assessed in 54 patients with spina bifida, 57 mothers of patients, 93 control children, and 86 mothers of controls. The QQ genotype (present in 17% and 7% of the control and case mothers, respectively, and in 12% and 6% of the control and case children, respectively) was associated with a decreased risk of NTD (odds ratios of 0.52 (95% CI 0.13-2.05) for children and 0.37 (95% CI 0.11-1.22) for mothers). The small sample size limited the statistical power of the analyses, but these decreases, although not statistically significant, are compatible with a protective effect. We did not observe statistically-significant genotype-dependent differences in plasma homocysteine, although women with the QQ genotype did have lower homocysteine; in children, the mean homocysteine level was higher in the QQ group. This inconsistency could be explained by the fact that age is a strong determinant of homocysteine in children and the QQ group was on average older than the other genotype groups. Our study suggests that the Q allele of the R239Q mutation may decrease risk of the condition. This warrants further investigation of its relationship with the development of NTD.

Amino Acid Substitution↗
PubMed2003

Coeliac disease patients carry conserved HLA-DR3-DQ2 haplotypes revealed by association of TNF alleles.

Certain HLA-DQ alleles are known to contribute to predisposition to coeliac disease (CD). The existence of additional independent risk-modifying loci in the HLA complex is still being debated. The DR3-DQ2 haplotype has been studied most, but the evidence is conflicting. The discrepancies may stem from the absence of such an effect, insufficient statistical power to detect an effect (i.e. small studies) and/or incomplete control of linkage disequilibrium (LD) to the neighbouring DQ-loci, known to elicit a strong effect. In the present study, we aimed to undertake a statistically high-powered family-based analysis, fully controlling effects of LD between the major DQ-risk haplotypes and neighbouring candidate loci. We investigated five markers on DR3-DQ2, DR5-DQ7 and DR7-DQ2 haplotypes in 327 Norwegian and Swedish families. Our primary finding was that TNF-308A ( TNF2) was significantly associated on the DR3-DQ2 haplotype [stratum specific odds ratio (OR) = 2.40 (1.25-4.48), Pc = 0.009, where P(c) = Pn and n = number of tests performed]. Furthermore, we confirmed earlier indications that LD between TNF2 and DQA1*05-DQB1*02 on the DR3 haplotype is more strongly maintained in family-based cases than family-based controls. In conclusion, we confirmed in this study, the largest of its kind, that additional CD risk factors independent of DQ2 alleles do exist on the DR3 haplotype.

Case-Control Studies↗
PubMed1984

Assessment of "Average of Normals" quality control procedures and guidelines for implementation.

The capabilities of "Average of Normals" control procedures have been assessed by determining power functions, graphs of the probability of error detection versus the size of analytic error. The power functions indicate that the most important determinants of statistical power are the ratio of the standard deviation of the patient population (Sp) to the analytic standard deviation (Sa), Sp/Sa; the number of data points averaged (N); the control limits (probability for false rejection); truncation limits for selecting the population; and the magnitude of the population lying outside the truncation limits. General guidelines for the implementation of "Average of Normals" are provided, along with a nomogram for the selection of N as a function of Sp/Sa and the probability of error detection. Optimal performance of these procedures may require simulation studies on a per analyte basis.

Computers↗
PubMed1998

Use of whole-body plethysmography to compare bronchodilator inhaler efficacy.

Whole-body plethysmography is not included in guidelines from regulatory authorities for the development of treatments or delivery devices for lung disease, despite its potential advantages compared to spirometry. Two separate studies were undertaken to assess the use of specific airway conductance (sGaw) as a pharmacodynamic endpoint for the comparison of two bronchodilator delivery systems (a novel dry powder inhaler and a standard metered dose inhaler). The first pilot study involved delivery of a single dose of salbutamol (200 micrograms) to 12 healthy volunteers and determination of sGaw up to 120 min after treatment. The second study involved delivery of cumulative doses of salbutamol (100, 200 and 400 micrograms) to 19 healthy volunteers with demonstrated reversibility of sGaw to the bronchodilator and measurement of sGaw up to 240 min after treatment. In both studies, increases in sGaw after treatment were significant compared to placebo and larger than the recorded increases in FEV1. Increases in sGaw were similar for both delivery devices and support the therapeutic equivalence of the two products. Power calculations indicated that the second study had appropriate statistical power to discriminate between treatments. It is concluded that the assessment of sGaw in healthy volunteers may be a useful and sensitive pharmacodynamic endpoint for use in the development of bronchodilators and their delivery devices.

Adult↗
PubMed2001

Differences in lost letter responses from a seaside city.

Of 75 letters "lost" in the Florida Panhandle, 33 (44%) were returned in the mail by the finders (the altruistic response). Addressees' affiliations were significantly associated with different rates of return; fewer emotive Intercontinental Gay and Lesbian Outdoors Organization addressees were returned than nonemotive ones. The technique for power analysis by Gillett (1996) was applied to data from an earlier study and indicated our sample of 75 subjects would still yield a desired power level, i.e., 80, for the likely effect sizes. Statistical power was .83, and the effect was medium in size at .34.

Adult↗