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PubMed2003

Nuclear DNA analyses in genetic studies of populations: practice, problems and prospects.

Population-genetic studies have been remarkably productive and successful in the last decade following the invention of PCR technology and the introduction of mitochondrial and microsatellite DNA markers. While mitochondrial DNA has proven powerful for genealogical and evolutionary studies of animal populations, and microsatellite sequences are the most revealing DNA markers available so far for inferring population structure and dynamics, they both have important and unavoidable limitations. To obtain a fuller picture of the history and evolutionary potential of populations, genealogical data from nuclear loci are essential, and the inclusion of other nuclear markers, i.e. single copy nuclear polymorphic (scnp) sequences, is clearly needed. Four major uncertainties for nuclear DNA analyses of populations have been facing us, i.e. the availability of scnp markers for carrying out such analysis, technical laboratory hurdles for resolving haplotypes, difficulty in data analysis because of recombination, low divergence levels and intraspecific multifurcation evolution, and the utility of scnp markers for addressing population-genetic questions. In this review, we discuss the availability of highly polymorphic single copy DNA in the nuclear genome, describe patterns and rate of evolution of nuclear sequences, summarize past empirical and theoretical efforts to recover and analyse data from scnp markers, and examine the difficulties, challenges and opportunities faced in such studies. We show that although challenges still exist, the above-mentioned obstacles are now being removed. Recent advances in technology and increases in statistical power provide the prospect of nuclear DNA analyses becoming routine practice, allowing allele-discriminating characterization of scnp loci and microsatellite loci. This certainly will increase our ability to address more complex questions, and thereby the sophistication of genetic analyses of populations.

Animals↗
PubMed2001

Evaluation of three screening tests and a risk assessment model for diagnosing peripheral neuropathy in the diabetes clinic.

OBJECTIVE: with the aim of evaluating predictive power, three simple screening tests as alternates to nerve conduction tests for diagnosing diabetic peripheral neuropathy (DPN) were investigated. Results of the screening tests, along with the subjects' demographic and clinical characteristics, were planned as the variables for the development of a risk assessment tool for predicting DPN. DESIGN: this is a cross-sectional multi-group comparison study. The study utilized a predictive model derived from one subset of the study population, and prospectively tested in the other subset to predict the presence of neuropathy. SETTING: Diabetic Neuropathy Research Clinic of the Toronto General Hospital and University Health Network in Toronto, Ontario, Canada from June 1998 to August 1999. SAMPLE POPULATION: data come from 478 subjects consisting of non-diabetic reference subjects, and patients with type 1 and type 2 diabetes mellitus. OUTCOMES MEASURES: nerve conduction studies (NCS) comprised the primary defined outcome. The three screening sensory tests examined in the study were the Semmes-Weinstein 10 g monofilament examination (SWME), superficial pain sensation, and vibration by the on-off method. RESULTS: the three screening tests are significantly and positively correlated with NCS. An increase in the number of insensate responses in the screening test is associated with an increase in the abnormal NCS score. The strength of the association between NCS and each sensory test was greater when the neuropathy severity stage of the subject was added to the model. Both the SWME and vibration by the on-off method tests demonstrated sufficient statistical power to differentiate non-diabetic control subjects from subjects with diabetes, as well as to differentiate subjects with diabetes with and without neuropathy. These two tests, when compared with NCS, also demonstrated acceptable diagnostic performance characteristics in terms of high sensitivity and specificity, total number of correctly predicted cases, and receiver-operating characteristic curves. CONCLUSION: this data, through the development of a model involving training and validation sets, demonstrates that the knowledge of clinical risk factors alters the interpretation of sensory tests for DPN. This finding lends further support to the validity of simple sensory testing maneuvers in the conditional diagnosis of DPN. We recommend annual screening with either the SWME or vibration by the on-off method in the primary care and diabetes clinics.

Cross-Sectional Studies↗
PubMed1989

The use of attributable fraction in the design and interpretation of epidemiologic studies.

Because of the etiologic heterogeneity present in many diseases and the interaction among causal factors in the development of disease, relative risks relating any one exposure to a disease may be low, especially in the presence of common exposures. Nevertheless, in the design of epidemiologic studies, arbitrary values of relative risks are often used to determine the sample size required to detect an association between a particular exposure and a disease outcome. Such an approach may not yield adequate statistical power to detect an association. In this commentary, the authors point out the value of using the attributable fraction to determine an appropriate value of relative risk to use for sample size calculations. The approach is particularly useful in cluster investigations where the magnitude of the expected attributable fraction can be readily estimated from the observed and expected rates of disease. Specification of an attributable fraction is also useful in the design of case-control studies of etiologically heterogeneous diseases, especially when common exposures are suspected. Finally, the relationship among attributable fraction, relative risk and exposure frequency is valuable in interpreting results of an epidemiologic study and gaining insight into the differences in relative risk estimates found in various studies.

Epidemiologic Methods↗
PubMedDate not supplied

Commingling and segregation analysis of serum uric acid in five North American populations: the Lipid Research Clinics family study.

The role of major genes in the expression of serum uric acid (UA) levels was investigated in data collected from five clinics of the Lipid Research Clinics (LRC) family study. Over 2,000 randomly ascertained individuals were analyzed. The UA distributions were homogeneous among the five LRC clinics and between the parental and offspring generations. This result suggested that the data could be pooled across clinics, thereby increasing the statistical power associated with larger sample sizes for testing various null hypotheses. Additionally, a mixture of three normal distributions best characterized the combined-clinics data. Segregation patterns were examined in the untransformed data, as well as in a more conservative (and biologically meaningful) log transformation. Prior to log transformation, both major and multifactorial effects were detected. The major effect was not transmissible, i.e., was not compatible with Mendelian transmission, and accounted for 39% of the variance in UA levels. However, after the log transform was applied to the data and the segregation analysis was repeated, support for the major effect disappeared altogether and only the multifactorial component remained, accounting for 50% of the variation in offspring and 19% in patients.

Adolescent↗
PubMed2000

Subject-domain approach to the study of air pollution effects on schoolchildren's illness absence.

In this paper, the authors propose a new statistical modeling technique, the subject-domain approach, which is theoretically proven to be equivalent to the time-domain approach in detecting an association between exposure and response with time trends. The authors use an empirical data set from a school absence monitoring study conducted during the 1994-1995 school year in Taiwan to demonstrate this subject-domain approach's application to environmental epidemiologic studies. Because the subject-domain models can control the influential personal confounding factors in the models, they show greater statistical power than the traditional time-domain approaches in determining the relation between air pollution and illness absences. The authors' models found that the schoolchildren's risks of illness absence were significantly related to acute exposures to nitrogen dioxide and nitrogen oxides with a 1-day lag (p < 0.01) at levels below the World Health Organization's guidelines. By contrast, the authors could not detect significant associations between air pollution and schoolchildren's absenteeism using time-domain approaches. Such findings imply that the models built on subject domain may be a general solution to the problem of the ecologic fallacy, which is commonly encountered in environmental and social epidemiologic studies.

Absenteeism↗
PubMed2002

Inferring relationships between pairs of individuals from locus heterozygosities.

BACKGROUND: The traditional exact method for inferring relationships between individuals from genetic data is not easily applicable in all situations that may be encountered in several fields of applied genetics. This study describes an approach that gives affordable results and is easily applicable; it is based on the probabilities that two individuals share 0, 1 or both alleles at a locus identical by state. RESULTS: We show that these probabilities (zi) depend on locus heterozygosity (H), and are scarcely affected by variation of the distribution of allele frequencies. This allows us to obtain empirical curves relating zi's to H for a series of common relationships, so that the likelihood ratio of a pair of relationships between any two individuals, given their genotypes at a locus, is a function of a single parameter, H. Application to large samples of mother-child and full-sib pairs shows that the statistical power of this method to infer the correct relationship is not much lower than the exact method. Analysis of a large database of STR data proves that locus heterozygosity does not vary significantly among Caucasian populations, apart from special cases, so that the likelihood ratio of the more common relationships between pairs of individuals may be obtained by looking at tabulated zi values. CONCLUSIONS: A simple method is provided, which may be used by any scientist with the help of a calculator or a spreadsheet to compute the likelihood ratios of common alternative relationships between pairs of individuals.

DNA Fingerprinting↗
PubMed2006

Two closely related species of desert carpenter ant differ in individual-level allocation to fat storage.

Comparison of closely related species that differ in their life histories is a powerful method for studying the underlying physiological mechanisms contributing to life-history variation. I investigated whether two closely related members of the Camponotus festinatus species complex of desert carpenter ants, C. nr. festinatus Desert Light and C. nr. festinatus Desert Dark, differed in their life-history tactics with respect to fat storage. Newly mated queens were collected in the field, and colonies were reared under common conditions in the laboratory for 2 yr before sampling. I show that the two species differ in fat storage at the individual level. While the basic scaling relationship between lean mass and fat content did not differ between the two species, Dark workers and soldiers stored significantly more fat per unit lean mass than Light workers or soldiers. There were no significant demographic differences in the proportions of workers or soldiers involved in fat storage between the two species, although there was a trend toward Light colonies having a greater proportion of soldiers storing large amounts of fat. There was also no significant difference in the total amount of fat stored by the two species at the colony level. The detection of strong individual-level effects but no colony-level effects was likely due to the low statistical power of colony-level analyses. Showing that these two closely related species differ in fat storage at the individual level in a common environment demonstrates their utility as a model for understanding the physiological and behavioral mechanisms regulating life-history variation in fat storage in ants.

Adipose Tissue↗
PubMedDate not supplied

Making sense of noninferiority: a clinical and statistical perspective on its application to cardiovascular clinical trials.

Active control noninferiority trials are being used with increasing frequency in new drug or device development when standard placebo-controlled trials are considered unethical. Nevertheless, the design and analysis of these trials are founded on a number of assumptions and arbitrary criteria that are generally not well understood or justifiable. Trials designed to show noninferiority require an appropriate reference population, a proven active control and dose, an appropriate margin of noninferiority that is clinically relevant and statistically justifiable, a high level of adherence to treatment, and adequate statistical power to reliably conclude that a treatment is truly noninferior and therefore effective. Accordingly, if noninferiority trials are to be applied to clinical and regulatory decisions regarding the marketing and use of new treatments, the assumptions must be made explicit and their influence on the resultant conclusions must be assessed rigorously. When conservative criteria were applied to each of the key assumptions underlying 2 representative noninferiority trials, they materially undermined the conclusions regarding noninferiority failing to confirm reported conclusions regarding noninferiority despite enthusiastic dissemination and acceptance of the results. Because the clinical, regulatory, and economic impact of active control noninferiority trials is substantial, robust criteria should be used routinely in their design, analysis, and interpretation to reach their intended objectives and to keep them from becoming wasted efforts.

Anticoagulants↗
PubMed1991

Bladder and liver tumorigenesis induced by 2-acetylaminofluorene in different F1 mouse hybrids: variation within genotypes and effects of using more than one genotype on risk assessment.

Several F1 mouse hybrids were used in a chronic bioassay to determine whether such an experimental design would provide greater statistical power than using only the B6C3F1 hybrid. For this purpose, the dose response of formation of hepatocellular and bladder tumors after 30 mo of feeding 2-acetylaminofluorene (2-AAF) in the diet was assessed in 4 F1 mouse hybrids, including the B6C3F1 hybrid. No strain background-related differences in frequency of bladder neoplasms between any F1 hybrids were detected. Bladder tumors occurred only at the highest 2-AAF dose in female mice. In males the lowest dose was already sufficient to induce bladder neoplasms with incidences of 25-48% adjusted for different nontumor mortality patterns across doses. No marked strain-related differences in hepatocellular tumor rates were apparent in either sex. Higher frequencies of hepatocellular neoplasms were observed among the untreated control males of the B6C3, AY, and CVA F1 hybrids than among the comparable females. Among treated mice, the lowest 2-AAF dose increased liver tumor incidence, more so among the females than among the males. The different background genomes resulted in somewhat different risk assessments for liver tumor formation in males due to differences in the time-to-tumor curves. Except for the much higher background liver tumor rate in the CVY mice, the adjusted liver tumor incidences were similar across the four hybrids. Hence, the levels of statistical significance obtained for dose-response trends and comparisons of treated and control groups were similar using 48 animals per dose groups with B6C3 mice, or combinations of 24 animals per dose from 2 genotypes, or 12 animals per dose from the 4 hybrid genotypes. Estimates of carcinogenic potency for bladder tumors were similar, within a factor of two, across the four hybrids. However, estimates of liver tumor potency across genotypes varied by a factor of two and six for females and males, respectively. Thus, the mean of cancer potency estimates across these genotypes would be more representative for mice than results from any single genotype. As in chronic carcinogenesis studies with other test agents, neoplasms developed in only a certain proportion, rather than in all, of the genetically identical animals exposed to a given dose of the toxicant for the same length of time under the same controlled environmental conditions. This phenotypic variability in toxic responses may reflect differential regulation of gene expression among the genetically identical test animals.

2-Acetylaminofluorene↗
PubMed2006

A meta-analysis of safety and effectiveness of perioperative beta-blocker use for the prevention of cardiac events in different types of noncardiac surgery.

OBJECTIVE: Perioperative beta-blocker therapy has been proposed to improve outcome. Most of the trials conducted, however, lacked statistical power to evaluate the incidence of hard cardiac events and the relationship to the type of surgery. Therefore, we conducted a meta-analysis of all randomized controlled trials in which beta-blocker therapy was evaluated. METHODS: An electronic search of published reports on Medline was undertaken to identify studies published between January 1980 and November 2004 in English language journals. All studies reported on at least one of three endpoints: perioperative myocardial ischemia, perioperative nonfatal myocardial infarction, and cardiac mortality. Type of surgery, defined as low, intermediate, and high risk according to the American College of Cardiology/American Heart Association guidelines, was noted. RESULTS: In total, 15 studies were identified, which enrolled 1,077 patient. No significant differences were observed in baseline clinical characteristics between patients randomized to beta-blocker therapy and control/placebo. Beta-blocker therapy was associated with a 65% reduction in perioperative myocardial ischemia (11.0% vs. 25.6%; odds ratio 0.35, 95% confidence interval 0.23-0.54; P<0.001). Furthermore, a 56% reduction in myocardial infarction (0.5% vs. 3.9%, odds ratio 0.44, 95% confidence interval 0.20-0.97; P=0.04) and a 67% reduction (1.1% vs. 6.1%, odds ratio 0.33, 95% confidence interval 0.17-0.67; P=0.002) in the composite endpoint of cardiac death and nonfatal myocardial infarction were observed. No statistical evidence was observed for heterogeneity in the treatment effect in subgroups according to type of surgery (P for heterogeneity 0.2). CONCLUSION: This meta-analysis shows that beta-blocker use in noncardiac surgical procedures is associated with a significant reduction of perioperative cardiac adverse events.

Adrenergic beta-Antagonists↗
PubMed1996

Case-control study on maternal residential proximity to high voltage power lines and congenital anomalies in France.

The literature indicates that exposure to electro-magnetic fields (EMF) may result in an increased incidence of cancer and spontaneous abortion. The aim of the present study was to determine whether living closer to high voltage power lines (HVPL) increased the risk of congenital anomalies. We studied residential exposure in any municipality in the Central-East Region of France where there was at least one residence within 500 metres of a HVPL. This was a matched case-control design. The cases consisted of all children with congenital anomalies, identified to the population-based registry in Central-East France between 1988-91. We chose two random controls, matched for birth year and municipality, for each case. For every case and control, we measured the distance from the HVPL to the maternal residence at the time of birth of the child as a surrogate for EMF exposure. Using 100 metres from an HVPL as the cut-point between exposure and non-exposure to electro-magnetic fields produced by HVPL, yielded an odds ratio of 0.95 (95% (confidence interval) CI: 0.45-2.03). Using 50 metres as the cut-point, yielded an OR of 1.25 (95% CI: 0.49-3.22). Among the 11 cases within 100 metres, there were 2 children with chromosomal anomalies, but otherwise there was no pattern in the occurrence of specific anomalies. These data indicate a lack of association between distance to HVPL and the total number of congenital anomalies. This study does not have enough statistical power to determine whether the prevalence of a specific congenital anomaly is significantly increased as a result of living near a HVPL.

Case-Control Studies↗
PubMed2005

Birth defects after prenatal exposure to antiepileptic drugs.

BACKGROUND: Exposure to antiepileptic drugs (AEDs) in the first trimester of pregnancy has been associated with an increased risk of major congenital anomalies (MCAs) in offspring. Most of the studies, however, have been fraught with methodological shortcomings, and differences in ascertainment methods and classifications prevent meaningful data pooling. Individual studies lacked the statistical power to assess comparative risks associated with specific AEDs. RECENT DEVELOPMENTS: Several larger-scale studies, including collaborative multinational registries, have been set up to compare MCA risks associated with different treatments, including newer generation AEDs. Results have largely been consistent with the notion that monotherapy with the most commonly used AEDs is associated with an increase in risk of MCAs by two to three times, and that the magnitude of risk increases in offspring exposed to polytherapy. Available evidence does not suggest that epilepsy per se is associated with a major increase in the risk of MCAs. Almost all studies have suggested that exposure to valproic acid is associated with a greater incidence of MCAs than other AEDs. Valproic acid is also the only AED for which a dose-dependency has been confirmed in several studies: the increase in risk of MCAs, compared with other AEDs, is especially evident at doses above 800-1000 mg/day. Data from the North American registry have suggested that phenobarbital may also have a higher teratogenic risk compared with AEDs other than valproic acid, but evidence remains inconclusive. Information about effects on fetuses of newer generation AEDs other than lamotrigine and oxcarbazepine is scant. Although teratogenic effects of lamotrigine and oxcarbazepine have not been established with certainty, none of the investigations to date identified any statistically significant difference in rates of MCAs between infants exposed to lamotrigine or oxcarbazepine and infants exposed to carbamazepine. In the case of lamotrigine, moreover, a positive correlation between maternal dose and rates of MCAs has been identified. WHERE NEXT?: Collaborative pregnancy registries worldwide are at work to fill remaining gaps in knowledge. Issues to be addressed include the comparative risks associated with phenobarbital, with low-dose valproic acid, with newer generation AEDs, and with specific AED combinations; the influence of potential confounders; and the interaction of AED-associated risks with other risk factors, such as genetic profiles. Large scale studies may also clarify whether individual AEDs differ in their ability to cause specific anomalies. Finally, studies are urgently needed to investigate other potential adverse effects of AED exposure, with special reference to effects on postnatal intellectual development.

Abnormalities, Drug-Induced↗
PubMed2001

A prospective randomized comparison of laparoscopic appendectomy with open appendectomy: Clinical and economic analyses.

BACKGROUND: Previous randomized studies of laparoscopic appendectomy produced conflicting recommendations, and the adequacy of sample sizes is generally unknown. We compared clinical and economic outcomes after laparoscopic and open appendectomy in a sample of predetermined statistical power. METHODS: A pre-study power analysis suggested that 200 randomized patients would yield 80% power to show a mean decrease of 1.3 days' hospitalization. One hundred ninety-eight patients with a preoperative diagnosis of acute appendicitis were randomized prospectively to laparoscopic or open appendectomy. Economic analysis included billed charges, total costs, direct costs, and indirect costs associated with treatment. RESULTS: Laparoscopic appendectomy took longer to perform than open appendectomy (median, 107 vs 91 minutes; P <.01) and was associated with fewer days to return to a general diet (mean, 1.6 versus 2.3 days; P <.01), a shorter duration of parenteral analgesia (mean, 1.6 versus 2.2 days; P <.01), fewer morphine-equivalent milligrams of parenteral narcotic (median, 14 mg versus 34 mg; P =.001), a shorter postoperative hospital stay (mean, 2.6 versus 3.4 days; P <.01), and earlier return to full activity (median, 14 versus 21 days; P <.02). However, operative morbidity and time to return to work were comparable. Billed charges and direct costs were not significantly different in the 2 groups ($7711 versus $7146 and $5357 versus $4945, respectively), but total costs (including indirect costs) of laparoscopic appendectomy were, on average, nearly $2400 less, given the shorter length of stay and abbreviated recuperative period ($11,577 versus $13,965). Subgroup analyses suggested the benefit of a laparoscopic approach for uncomplicated appendicitis and for patients with active lifestyles. CONCLUSIONS: While laparoscopic appendectomy is associated with statistically significant but clinically questionable advantages over open appendectomy, a laparoscopic approach is relatively less expensive. The estimated difference in total costs of treatment (direct and indirect costs) was at least $2000 in more than 60% of the bootstrapped iterations. The economic significance and implications favoring a laparoscopic approach cannot be ignored.

Appendectomy↗
PubMed2004

Evaluating associations of haplotypes with traits.

Haplotypes have played a major role in the study of highly-penetrant single-gene disorders, and recent evidence that the human genome has hot-spots and cold-spots for recombination have suggested that haplotype-based methods may play a key role in the study of common complex traits. This report reviews the motivation of using haplotypes for the study of the genetic basis of human traits, ranging from biologic function, to statistical power advantages of haplotypes, to linkage disequilibrium fine-mapping. Recent developments of regression models for haplotype analyses are reviewed, offering a synthesis of current methods, as well as their limitations and areas that require further research. Regression models provide significant advantages, such as the ability to control for non-genetic covariates, the effects of the haplotypes can be modeled, step-wise selection can be used to screen for a subset of markers that explain most of the association, haplotype x environment interactions can be evaluated, and regression diagnostics are well developed. Despite these strengths, the current regression methods tend to lack the sophisticated population genetic perspectives offered by coalescent and other similar approaches. Future work that links regression methods with population genetic models may prove beneficial.

Chromosome Mapping↗
PubMed2006

Constraints for genetic association studies imposed by attributable fraction and familial risk.

Candidate gene studies have become very popular but some of their implicit constraints, such as the familial risk and the population attributable fraction (PAF) conferred by the gene under study, are poorly understood. We model here these parameters for susceptibility genes in terms of genotype relative risk (GRR), allele frequency and statistical power in simulated genetic association studies, assuming 500 or 2000 case-control pairs and different modes of inheritance. The results show that the common association studies on genes with minor allele frequency >10% have sufficient power to detect disease-causing variants conferring PAFs >10%, which can be compared to known genes, such as BRCA1 with a PAF of 1.8%. Yet, common low-risk variants confer low familial relative risks (FRRs), typically <1.1. The models show that candidate gene studies may be able to identify genes conferring close to 100% of the PAF, but they may not explain the empirical FRRs. In order to explain FRRs, rare, high-penetrant genes or interacting combinations of common variants need to be uncovered. However, the candidate gene studies for common alleles do not target this class of genes. The results may challenge the common disease-common variant hypothesis, which posits common variants with low GRRs and large PAFs, however failing to accommodate the empirical FRRs.

Case-Control Studies↗
PubMed1995

Multiple trait analysis of genetic mapping for quantitative trait loci.

We present in this paper models and statistical methods for performing multiple trait analysis on mapping quantitative trait loci (QTL) based on the composite interval mapping method. By taking into account the correlated structure of multiple traits, this joint analysis has several advantages, compared with separate analyses, for mapping QTL, including the expected improvement on the statistical power of the test for QTL and on the precision of parameter estimation. Also this joint analysis provides formal procedures to test a number of biologically interesting hypotheses concerning the nature of genetic correlations between different traits. Among the testing procedures considered are those for joint mapping, pleiotropy, QTL by environment interaction, and pleiotropy vs. close linkage. The test of pleiotropy (one pleiotropic QTL at a genome position) vs. close linkage (multiple nearby nonpleiotropic QTL) can have important implications for our understanding of the nature of genetic correlations between different traits in certain regions of a genome and also for practical applications in animal and plant breeding because one of the major goals in breeding is to break unfavorable linkage. Results of extensive simulation studies are presented to illustrate various properties of the analyses.

Algorithms↗
PubMed2000

Seasonal and biological variation of blood concentrations of total cholesterol, dehydroepiandrosterone sulfate, hemoglobin A(1c), IgA, prolactin, and free testosterone in healthy women.

BACKGROUND: Concentrations of physiological response variables fluctuate over time. The present study describes within-day and seasonal fluctuations for total cholesterol, dehydroepiandrosterone sulfate (DHEA-S), hemoglobin A(1c) (HbA(1c)), IgA, prolactin, and free testosterone in blood, and estimates within- (CV(i)) and between-subject (CV(g)) CVs for healthy women. In addition, the index of individuality, prediction intervals, and power calculations were derived. METHODS: A total of 21 healthy female subjects participated in the study. Using a random effects analysis of variance, we estimated CV(g) and total within-subject variation (CV(ti)), i.e., the combined within-subject and analytical variation, from logarithmically transformed data. Analytical variation was subtracted from CV(ti) to give CV(i). CV(i) was estimated from samples taken monthly during 1 year (CV(iy)), weekly during 1 month (CV(im)), and six times within 1 day (CV(id)). RESULTS: A cyclic seasonal variation was demonstrated for total cholesterol, DHEA-S, HbA(1c), prolactin, and free testosterone. Within-day variation was shown for prolactin and free testosterone. The overall mean values for the group and the variability (CV(iy) and CV(g)) were: 5.1 mmol/L, 13% [corrected], and 12% [corrected] for total cholesterol; 6.6 micromol/L, 20% [corrected], and 49% [corrected] for DHEA-S; 30% [corrected], 7.0% [corrected], and 7.5% [corrected] for HbA(1c)/hemoglobin(total); 2.1 g/L, 5.9%, and 13% for IgA; 136 mIU/L, 58% [corrected], and 63% [corrected] for prolactin; and 5.4 pmol/L, 55% [corrected], and 68% [corrected] for free testosterone. CONCLUSIONS: Collecting samples at specific hours of the day or times of the year may reduce high biological variation. Alternatively, the number of individuals may be increased and a paired study design chosen to obtain adequate statistical power.

Adult↗
PubMed2004

Combined linkage and association tests in mx.

Statistical methods aimed at the detection of genes for quantitative traits suffer from two problems: (i) when a linkage approach is employed, relatively large sample sizes are usually required; and (ii) when an association approach is employed, effects of population stratification may blur genuine locus-trait associations. The variance components method proposed by Fulker et al. (1999) addressed both these problems; it is statistically powerful because it involves a combined analysis of linkage and association and can include information from multiplex families, which reduces the overall amount of necessary individual genotypes. In addition, it includes an explicit test for the presence of spurious association. After a brief illustration of the various ways in which population stratification may affect locus-trait associations, the implementation in Mx (Neale, 1997) of the method as proposed by Fulker et al. (1999) is discussed and illustrated. In addition, an extension to this method is proposed that allows the use of (variable) sibship sizes greater than two, the estimation of additive and dominance association effects, and the use of multiple alleles. These extensions can be implemented when parental genotypes are available or unavailable.

Alleles↗