Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “phenotypes”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMed2004

Subclasses of low-density lipoprotein and very low-density lipoprotein in familial combined hyperlipidemia: relationship to multiple lipoprotein phenotype.

OBJECTIVE: The present study addresses the presence of distinct metabolic phenotypes in familial combined hyperlipidemia (FCHL) in relation to small dense low-density lipoprotein (sd LDL) and very low-density lipoprotein (VLDL) subclasses. METHODS AND RESULTS: Hyperlipidemic FCHL relatives (n=72) were analyzed for LDL size by gradient gel electrophoresis. Pattern B LDL (sd LDL, particle size <258 A) and pattern A LDL (buoyant LDL, particle size > or =258 A) were defined. Analyses showed bimodal distribution of LDL size associated with distinct phenotypes. Subjects with predominantly large, buoyant LDL showed a hypercholesterolemic phenotype and the highest apo B levels. Subjects with predominantly sd LDL showed a hypertriglyceridemic, low high-density lipoprotein (HDL) cholesterol phenotype, with moderately elevated apoB, total cholesterol level, and LDL cholesterol level. Subjects with both buoyant LDL and sd LDL (pattern AB, n=7) showed an intermediate phenotype, with high normal plasma triglycerides. VLDL subfraction analysis showed that the sd LDL phenotype was associated with a 10-times higher number of VLDL1 particles of relatively lower apo AI and apo E content, as well as smaller VLDL2 particles, in combination with increased plasma insulin concentration in comparison to pattern A. CONCLUSIONS: The present observations underscore the importance of the VLDL triglyceride metabolic pathway in FCHL as an important determinant of the phenotypic heterogeneity of the disorder.

Adult↗
PubMed1993

Genetics of LDL subclass phenotypes in women twins. Concordance, heritability, and commingling analysis.

Low density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small LDL as determined by gradient gel electrophoresis, has been associated with increased risk of coronary heart disease and an atherogenic lipoprotein profile. Previous studies employing complex segregation analysis have demonstrated a major, single gene effect on the inheritance of this phenotype in families. Recently, linkage between this phenotype and variation at the LDL receptor locus on chromosome 19 has been reported. However, variation in LDL subclass phenotypes has also been associated with age, gender, diabetes status, beta-blocker medication, and diet. The present study further evaluates the relative importance of genetic and nongenetic influences on LDL subclass phenotypes and on LDL peak particle diameter (as a reflection of the size of the major LDL subclass) in monozygotic and dizygotic women twin pairs. The analysis is based on 203 monozygotic and 145 dizygotic pairs of adult female twins who participated in the second examination of the Kaiser Permanente Women Twins Study. The average age was 51 years at this exam and 90% were white. Concordance analysis revealed that monozygotic cotwins shared LDL subclass phenotypes more frequently than dizygotic cotwins, and this was confirmed using logistic regression analysis after controlling for potential confounding factors. Heritability analyses suggested that approximately one third to one half of the variation in LDL peak particle diameter, a continuous variable reflecting LDL size, could be attributed to genetic influences. Commingling analysis of the frequency distribution of LDL peak particle diameter identified three distinct subgroups of subjects, one of which corresponded to those subjects with LDL subclass phenotype B.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗
PubMed2000

Genetic determinants of hemostasis phenotypes in Spanish families.

BACKGROUND: Recent studies have described genetic mutations that affect the risk of thrombosis as a result of abnormal levels of such hemostatic parameters as protein C, protein S, and the activated protein C resistance ratio. Although these mutations suggest that genes play a part in determining variability in some hemostasis-related phenotypes, the relative importance of genetic influences on these traits has not been evaluated. METHODS AND RESULTS: The relative contributions of genetic and environmental influences to a panel of hemostasis-related phenotypes were assessed in a sample of 397 individuals in 21 extended pedigrees. The effects of measured covariates (sex, age, smoking, and exogenous sex hormones), genes, and environmental variables shared by members of a household were quantified for 27 hemostasis-related measures. All of these phenotypes showed significant genetic contributions, with the majority of heritabilities ranging between 22% and 55% of the residual phenotypic variance after correction for covariate effects. Activated protein C resistance ratio, activated partial thromboplastin time, and Factor XII showed the strongest heritabilities, with 71.3%, 83.0%, and 67.3%, respectively, of the residual phenotypic variation attributable to genetic effects. CONCLUSIONS: These results clearly demonstrate the importance of genetic factors in determining variation in hemostasis-related phenotypes that are components of the coagulation and fibrinolysis pathways and that have been implicated in risk for thrombosis. The presence of such strong genetic effects suggests that it will be possible to localize previously unknown genes that influence quantitative variation in these hemostasis-related phenotypes that may contribute to risk for thrombosis.

Adolescent↗
PubMed1993

Arterial smooth muscle cell phenotype in stroke-prone spontaneously hypertensive rats.

The aim of this study was to determine the phenotype of smooth muscle cells in the arteries of chronically hypertensive animals and to analyze the effects of treatments known to increase the survival of the animal without a clear effect on its hypertensive state. Stroke-prone spontaneously hypertensive rats (SHRSP) kept on a 1% sodium drinking solution were untreated or treated with one of two diuretics, indapamide (3 mg/kg per day) or hydrochlorothiazide (20 mg/kg per day), from 6 to 13 weeks of age. Phenotype was characterized by the immunolabeling of arteries with antibodies raised against a cellular form (EIIIA) of fibronectin, alpha-smooth muscle actin, and nonmuscle myosin. We demonstrated that phenotypes of smooth muscle cells of the SHRSP differ from those found in Wistar-Kyoto rats. The difference in phenotype is specific for the vessel type: ie, an increased expression of nonmuscle myosin in the aorta and of both EIIIA fibronectin and nonmuscle myosin in the coronary arteries. The two diuretics (1) had no effect on blood pressure, (2) prevented or did not prevent the increase in medial thickness, and (3) prevented changes in both smooth muscle cell phenotype and ischemic tissular lesions. Taken together, the results suggest that in SHRSP the changes in the phenotype of smooth muscle cells and the thickness of arteries are unrelated events. We propose that the maintenance of the contractile phenotype of the arterial smooth muscle cells could be an essential parameter involved in the prevention of the deleterious consequences characteristic of a severe hypertensive state.

Actins↗
PubMed1993

Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease. A case-control study.

BACKGROUND AND PURPOSE: Apolipoprotein E polymorphism may influence the early development of coronary artery disease. We investigated the putative role of apolipoprotein E phenotypes in cerebral infarction. METHODS: The apolipoprotein E phenotypes of 69 patients (mean +/- SD age, 72 +/- 11 years) who had suffered completed stroke or a transient ischemic attack and 68 sex- and age-matched control subjects free of cerebrovascular disease were determined by isoelectric focusing. The relative frequency of the apolipoprotein E phenotypes in the general population was estimated in 498 healthy blood donors (mean age, 37 years). RESULTS: The prevalences of hypertension, diabetes mellitus, obesity, and intermittent claudication were significantly higher in patients than in control subjects. Serum lipid and apolipoprotein B concentrations and the composition of very low density lipoproteins were not significantly different between patients and control subjects. Apolipoprotein A-I and E levels were significantly lower in patients. Cholesterol levels were higher in male patients than in male control subjects (5.10 +/- 1.46 versus 4.41 +/- 0.80 mmol/L; p = 0.036), and the ratio of apolipoprotein A-I to B was lower (0.77 +/- 0.29 versus 1.03 +/- 0.37; p < 0.001). The E3/E3 phenotype was more frequent in control subjects (85%) than in patients (72.5%; p < 0.05) and healthy blood donors (64%; p < 0.02). The E3/E2 phenotype was more frequent in patients (10.1%) than in control subjects (1.4%; p < 0.05). A stepwise logistic regression showed that the presence of stroke was significantly related to high blood pressure (p < 0.0001), low apo E levels (p < 0.008), obesity (p < 0.041), the apo E phenotype (p < 0.05), and diabetes mellitus (p < 0.05). CONCLUSIONS: The E3/E3 phenotype may protect against early vascular morbidity, and the epsilon 2 gene may be a risk factor for cerebrovascular morbidity, possibly related to diabetes, hypertension, and/or obesity.

Aged↗
PubMed1996

Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group.

This report describes the clinical characteristics of a group of 59 individuals with the PI*SZ phenotype and alpha 1-antitrypsin (alpha 1-AT) deficiency, identified during recruitment of a registry for subjects with severe alpha 1-antitrypsin deficiency. Currently, 1,129 individuals with levels of alpha 1-AT of 11 microM or below have been enrolled in this registry. Individuals with the SZ phenotype whose alpha 1-AT levels are at or below 11 microM will be followed in the registry; those whose levels exceeded 11 microM had baseline studies and are included in this report. Baseline pulmonary function tests included spirometry before and after an inhaled bronchodilator, diffusing capacity for carbon monoxide (DLCO), and chest roentgenograms. Among nonsmokers, subjects with the SZ phenotype demonstrated airflow obstruction less frequently than those with with the ZZ phenotype. Among ex- and current smokers, the frequency and severity of airflow obstruction was similar between SZ and ZZ subjects. Individuals with the SZ phenotype reported respiratory symptoms less frequently than did ZZ subjects. Overall, airflow obstruction was less common and milder among PI*SZ than PI*ZZ subjects. Cigarette smoking correlated more strongly with airflow obstruction among PI*SZ than PI*ZZ subjects. These observations indicate that in smokers, the PI*SZ phenotype confers a significant risk of the development of chronic obstructive pulmonary disease (COPD). Of itself, except in rare instances in nonsmoking individuals, the PI*SZ phenotype may confer little or no added risk of developing COPD.

Adult↗
PubMed2001

Transforming growth Factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway.

Myofibroblasts play an important role in the fibrogenic process of pulmonary fibrosis. Transforming growth factor (TGF)-beta is well known to induce the phenotypic modulation of fibroblasts to myofibroblasts; however, the intracellular signal regulating induction of the myofibroblastic phenotype of human lung fibroblasts (HLF) has not been determined. In the present study, we examined the role of the mitogen-activated protein kinase (MAPK) superfamily in inducing the phenotypic modulation of HLF to myofibroblasts characterized by alpha-smooth-muscle actin expression, in order to clarify this issue. The results showed that: (1) TGF-beta1 caused the phenotypic modulation of HLF to myofibroblasts in a dose- and a time-dependent manner; (2) TGF-beta1 induced increases in c-Jun-NH2- terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (Erk) phosphorylation and activity; (3) the inhibitors CEP-1347, SB 203580, and PD 98059 attenuated TGF-beta1-induced JNK, p38 MAPK, and Erk activity, respectively; and (4) CEP-1347, but not SB 203580 or PD 98059, attenuated the TGF-beta1-induced phenotypic modulation of HLF to myofibroblasts in a dose-dependent manner. These results indicate that TGF-beta1 is capable of inducing the myofibroblastic phenotype of HLF, and that JNK regulates the phenotypic modulation of TGF-beta1-stimulated HLF to myofibroblasts.

Carbazoles↗
PubMed1978

Pi phenotypes and the prevalence of chest symptoms and lung function abnormalities in workers employed in dusty industris.

Epidemiologic surveys were carried out on 1,138 white men employed in sawmills and grain elevator terminals in British Columbia. In addition to the administration of an occupational-health questionnaire and spirometry, Pi phenotype and the concentration of serum alpha1-antitrypsin were determined. Most of the workers (88.8 per cent) had the Pi M phenotype, whereas 8.0 per cent had the MS phenotype, and 2.7 per cent had the MZ phenotype. Very few workers (0.4 per cent) had other phenotypes. No differences were found among the 3 major phenotypes in the prevalence of chest symptoms and lung function abnormalities, even among cigarette smokers. These findings did not indicate that workers have the MZ phenotype with intermediate alpha-1-antitrypsin deficiency are particularly susceptible to the development of chronic obstructive lung disease under the conditions prevailing in these industries.

Adult↗
PubMed2000

Interferon-gamma production by specific lung lymphocyte phenotypes in silicosis in mice.

We recently described overproduction of interferon (IFN)-gamma by lung lymphocytes in mice with silicosis (11% of cells in air-control versus 19% of cells from silica-exposed mice; Davis and colleagues, Am. J. Respir. Cell Mol. Biol. 1999;20:813-824). We hypothesized that the increased IFN-gamma production might be due to selective enrichment of one lymphocyte phenotype. To test this hypothesis, small mononuclear cells from lung digest preparations of mice exposed 4 mo previously to cristobalite silica (70 mg/m(3), 12 d, 5 h/d) or to sham-air were stained for intracellular cytokines and surface antigen phenotypes, and examined by flow cytometry. Air-sham mouse lung digests included CD4(+) (16%) and CD8(+) (6%) T cells, gammadelta T-cell antigen receptor (TCR)(+) CD4(-)CD8(-) T cells (3%), natural killer (NK) cells (15%), B cells (6%), and macrophages (12%). The total number of lung lymphocytes was increased 1.7-fold in silicosis, but the phenotype frequencies did not change significantly. In the control lungs IFN-gamma was produced by three major phenotypes of lymphocytes: 5% of CD4(+) T cells, 5% of gammadelta-TCR(+) CD4(-)CD8(-) T cells, and 2% of NK cells. The percentage of each type producing IFN-gamma was increased 2- to 3-fold in silicosis. When multiplied by cell number, the increased percentages yielded a 3- to 5-fold increase in the total number of each IFN- gamma-producing phenotype in the lung. Our results demonstrate no selective phenotype enrichment but upregulated IFN-gamma production by at least three lymphocyte phenotypes. IFN-gamma may be an important signal driving lymphocyte differentiation and macrophage activation in silicosis.

Animals↗
PubMed1994

Phenotypic variability and incomplete penetrance of spontaneous fractures in an inbred strain of transgenic mice expressing a mutated collagen gene (COL1A1).

Phenotype variability and incomplete penetrance are frequently observed in human monogenic diseases such as osteogenesis imperfecta. Here an inbred strain of transgenic mice expressing an internally deleted gene for the pro alpha 1(I) chain of type I procollagen (COL1A1) was bred to wild type mice of the same strain so that the inheritance of a fracture phenotype could be examined in a homogeneous genetic background. To minimize the effects of environmental factors, the phenotype was evaluated in embryos that were removed from impregnated females 1 d before term. Examination of stained skeletons from 51 transgenic embryos from 11 separate litters demonstrated that approximately 22% had a severe phenotype with extensive fractures of both long bones and ribs, approximately 51% had a mild phenotype with fractures of ribs only, and approximately 27% had no fractures. The ratio of steady-state levels of the mRNA from the transgene to the level of mRNA from the endogenous gene was the same in all transgenic embryos. The results demonstrated that the phenotypic variability and incomplete penetrance were not explained by variations in genetic background or levels in gene expression. Instead, they suggested that phenotypic variation is an inherent feature of expression of a mutated collagen gene.

Animals↗
PubMedDate not supplied

Abdominal aortic aneurysm: association between haptoglobin phenotypes, elastase activity, and neutrophil count in the peripheral blood.

To investigate the role of genetic factors on susceptibility to atherosclerotic arterial disease, the influence of haptoglobin phenotypes (Hp) on serum elastase activity, neutrophil count, and elastin concentration in the aorta was measured in patients with abdominal aortic aneurysm (AAA; n=52) and aortoiliac atherosclerotic occlusive disease (AOD; n=37). Findings (serum elastase activity, peripheral blood neutrophil count) were compared to a control group (CG) of 37 subjects without atherosclerosis. Hp phenotyping performed by starch-gel electrophoresis produced a haptoglobin-hemoglobin complex of three phenotypes: Hp1-1, Hp2-2, and Hp2-1. Distribution of Hp phenotypes was similar in the three study groups (AAA, AOD, CG). Significant increases in serum elastase activity and neutrophil count was measured in Hp2-1 phenotype of AAA patients. Although the aorta wall of aneurysm patients contained less (p<0.001) elastin than that of AOD patients, no significant difference of aorta elastin concentration between the three Hp phenotypes, including Hp2-1, was measured. The postulated association of AAA susceptibility with Hp2-1 phenotype was supported by the study data that demonstrated an increase in serum elastase activity in patients undergoing AAA repair.

Aged↗
PubMed2000

Socioeconomic status, ABO phenotypes and risk of ischaemic heart disease: an 8-year follow-up in the Copenhagen Male Study.

OBJECTIVES: The association of socioeconomic status with the risk of ischaemic heart disease is only partly explained by the uneven distribution of conventional risk factors. We tested the hypothesis that an uneven socioeconomic distribution of ABO phenotypes could contribute to the explanation. DESIGN: A prospective study controlling for age and other relevant potential confounders: smoking, physical activity, wine consumption, height, weight, serum lipids, blood pressure, hypertension, type II diabetes, serum selenium concentration and soldering fumes exposure. SETTING: The Copenhagen Male Study, Denmark. STUDY PARTICIPANTS: Two thousand, nine hundred and ninety-three men aged 53-74 years without overt ischaemic heart disease. MAIN OUTCOME MEASURE: Incidence of ischaemic heart disease in an 8-year follow-up. RESULTS: Two hundred and forty-two men (8.1%) had a first ischaemic heart disease event. There was no association between socioeconomic status and the ABO blood group phenotypes and, in accordance with this, ABO phenotype was not a confounder for the association of socioeconomic status with the risk of ischaemic heart disease. However, ABO blood group was a strong risk or effect modifier. Only among men with the O phenotype was socioeconomic status (social classes IV and V versus social classes I, II and III) associated with a significant excess risk (relative risk 1.7, 95% confidence interval 1.1-2.7 and P = 0.02 after adjustment for confounders; the corresponding relative risks among the A and B/AB phenotypes comparing low social classes with the higher social classes were 1.08 (P = 0.77) and 1.08 (P = 0.89), respectively). CONCLUSION: ABO phenotypes did not contribute directly to the explanation of socioeconomic inequalities in the risk of ischaemic heart disease. However, the finding of ABO phenotypes being effect modifiers for the association of socioeconomic status with the risk of ischaemic heart disease may open up new possibilities of clarifying the roles of socioeconomic status and ABO blood group as cardiovascular disease risk factors.

ABO Blood-Group System↗
PubMed2006

Haptoglobin phenotype appears to affect the pathogenesis of American trypanosomiasis.

In Latin America, 16 million-18 million people are thought to be infected with Trypanosoma cruzi, the parasite that causes American trypanosomiasis. The pathophysiology of this disease, particularly that of its chronic phase, has yet to be fully elucidated. The major function of haptoglobin, an acute-phase plasma protein found in three different phenotypes (Hp1-1, Hp2-1 and Hp2-2), is to bind to free haemoglobin and so prevent the accumulation of reactive hydroxyl radicals and renal damage. The haptoglobin phenotype present can influence the severity and progression of many diseases, including infectious ones. The aim of the present study was to see if any haptoglobin phenotype could be associated with any of the various clinical forms of American trypanosomiasis, and so explore the possibility that haptoglobin and iron metabolism have a role in the pathophysiology of this disease. The Brazilian subjects investigated were either suffering from the 'indeterminate' (N=16), chronic cardiac (N=34), chronic digestive (N=13) or chronic 'combined' (i.e. cardiac plus digestive; N=29) forms of the disease or were apparently healthy blood donors from the same region as the patients (N=197). Haptoglobin phenotypes were determined by polyacrylamide-gel electrophoresis. Among the iron-related parameters investigated in the patients, only total iron-binding capacity and the serum concentration of haptoglobin differed significantly with haptoglobin phenotype. Compared with its frequency in the healthy controls, the Hp2-2 phenotype was much more frequent in the patients with any form of American trypanosomiasis, in the patients with the indeterminate form of the disease, and in the patients with the chronic combined form (P<or=0.0001 for each). It therefore appears that, in terms of the pathogenesis in those exposed to T. cruzi, possession of the 2-2 phenotype of haptoglobin may be detrimental.

Anemia↗
PubMed2001

Molecular basis of the adult i phenotype and the gene responsible for the expression of the human blood group I antigen.

The human blood group i and I antigens are characterized as linear and branched repeats of N-acetyllactosamine, respectively. Conversion of the i to the I structure requires the activity of I-branching beta-1,6-N-acetylglucosaminyltransferase (IGnT). Thus the blood group I gene is assigned to encode a beta-1,6-N-acetylglucosaminyltransferase; however, its identity has not been confirmed. The null phenotype of I, the adult i phenotype, provides a means to identify the I gene. Interestingly, the adult i phenotype has been noted to be associated with congenital cataracts in Asians. Molecular genetic studies of 3 adult i pedigrees are reported here. The results obtained on mutation detection within the 2 I-branching enzyme encoding genes, segregation analyses, and enzyme function assays identify molecular changes associated with the adult i phenotype. The adult i phenotype in 2 of the pedigrees studied resulted from 1043G-->A and 1148G-->A mutations, which predict Gly348Glu and Arg383His alterations, respectively, in the IGnT gene. These amino acid changes abolished the original GlcNAc-transferase activity. Deletion of the IGnT gene was observed in the person with adult i phenotype in the third pedigree. These findings suggest that the IGnT gene, first reported in 1993, is the candidate for the blood group I gene. Confirmation of the blood group I gene will further assist in the investigations of the molecular genetics that control I antigen expression in secretions and the molecular basis for the association of the adult i phenotype with congenital cataracts in Asians.

Adult↗
PubMed1997

Alpha1-antitrypsin phenotypes in patients with cryptogenic fibrosing alveolitis: a case-control study.

Cryptogenic fibrosing alveolitis (CFA) is an interstitial lung disease, which by definition is of unknown aetiology. Recent evidence has suggested that smoking and occupational exposure to dusts may be environmental risk factors for the disease, but there has been little research into potential host risk factors. One previous study has suggested that the prevalence of abnormal alpha1-antitrypsin phenotypes may be increased in patients with CFA. Since alpha1-antitrypsin is important in regulating inflammation within the lung in response to environmental exposures, such abnormalities may be of aetiological importance in this disease. We have compared the alpha1-antitrypsin phenotypes of 189 patients with CFA with 189 age-, sex-, and community-matched controls. This sample size was sufficient to provide more than 95% power to detect an odds ratio (OR) of 2.5. Alpha1-antitrypsin phenotype was established by isoelectric focusing, and the prevalence of abnormal phenotypes in cases and controls was compared by conditional logistic regression. Personal smoking histories were obtained by postal questionnaire. The prevalence of abnormal alpha1-antitrypsin phenotypes was similar in cases and controls (12.7 versus 15.3%; OR 0.88; 95% confidence interval 0.49-1.57; p=0.66). No interaction was found between the presence of abnormal alpha1-antitrypsin phenotypes and a history of smoking. We conclude that cryptogenic fibrosing alveolitis is not associated with abnormal alpha1-antitrypsin phenotypes.

Adult↗
PubMed2003

Identification of genes for complex disease using longitudinal phenotypes.

Using the simulated data set from Genetic Analysis Workshop 13, we explored the advantages of using longitudinal data in genetic analyses. The weighted average of the longitudinal data for each of seven quantitative phenotypes were computed and analyzed. Genome screen results were then compared for these longitudinal phenotypes and the results obtained using two cross-sectional designs: data collected near a single age (45 years) and data collected at a single time point. Significant linkage was obtained for nine regions (LOD scores ranging from 5.5 to 34.6) for six of the phenotypes. Using cross-sectional data, LOD scores were slightly lower for the same chromosomal regions, with two regions becoming nonsignificant and one additional region being identified. The magnitude of the LOD score was highly correlated with the heritability of each phenotype as well as the proportion of phenotypic variance due to that locus. There were no false-positive linkage results using the longitudinal data and three false-positive findings using the cross-sectional data. The three false positive results appear to be due to the kurtosis in the trait distribution, even after removing extreme outliers. Our analyses demonstrated that the use of simple longitudinal phenotypes was a powerful means to detect genes of major to moderate effect on trait variability. In only one instance was the power and heritability of the trait increased by using data from one examination. Power to detect linkage can be improved by identifying the most heritable phenotype, ensuring normality of the trait distribution and maximizing the information utilized through novel longitudinal designs for genetic analysis.

Cardiovascular Diseases↗
PubMed2005

Power and sample size calculations in the presence of phenotype errors for case/control genetic association studies.

BACKGROUND: Phenotype error causes reduction in power to detect genetic association. We present a quantification of phenotype error, also known as diagnostic error, on power and sample size calculations for case-control genetic association studies between a marker locus and a disease phenotype. We consider the classic Pearson chi-square test for independence as our test of genetic association. To determine asymptotic power analytically, we compute the distribution's non-centrality parameter, which is a function of the case and control sample sizes, genotype frequencies, disease prevalence, and phenotype misclassification probabilities. We derive the non-centrality parameter in the presence of phenotype errors and equivalent formulas for misclassification cost (the percentage increase in minimum sample size needed to maintain constant asymptotic power at a fixed significance level for each percentage increase in a given misclassification parameter). We use a linear Taylor Series approximation for the cost of phenotype misclassification to determine lower bounds for the relative costs of misclassifying a true affected (respectively, unaffected) as a control (respectively, case). Power is verified by computer simulation. RESULTS: Our major findings are that: (i) the median absolute difference between analytic power with our method and simulation power was 0.001 and the absolute difference was no larger than 0.011; (ii) as the disease prevalence approaches 0, the cost of misclassifying a unaffected as a case becomes infinitely large while the cost of misclassifying an affected as a control approaches 0. CONCLUSION: Our work enables researchers to specifically quantify power loss and minimum sample size requirements in the presence of phenotype errors, thereby allowing for more realistic study design. For most diseases of current interest, verifying that cases are correctly classified is of paramount importance.

Alzheimer Disease↗
PubMed2006

Integration of curated databases to identify genotype-phenotype associations.

BACKGROUND: The ability to rapidly characterize an unknown microorganism is critical in both responding to infectious disease and biodefense. To do this, we need some way of anticipating an organism's phenotype based on the molecules encoded by its genome. However, the link between molecular composition (i.e. genotype) and phenotype for microbes is not obvious. While there have been several studies that address this challenge, none have yet proposed a large-scale method integrating curated biological information. Here we utilize a systematic approach to discover genotype-phenotype associations that combines phenotypic information from a biomedical informatics database, GIDEON, with the molecular information contained in National Center for Biotechnology Information's Clusters of Orthologous Groups database (NCBI COGs). RESULTS: Integrating the information in the two databases, we are able to correlate the presence or absence of a given protein in a microbe with its phenotype as measured by certain morphological characteristics or survival in a particular growth media. With a 0.8 correlation score threshold, 66% of the associations found were confirmed by the literature and at a 0.9 correlation threshold, 86% were positively verified. CONCLUSION: Our results suggest possible phenotypic manifestations for proteins biochemically associated with sugar metabolism and electron transport. Moreover, we believe our approach can be extended to linking pathogenic phenotypes with functionally related proteins.

Computational Biology↗