Biomedical subjects

David V Conti

Publications and source records attributed to David V Conti.

At least 19 recordsLinked to original sources

PubMed2025

Genetic risk factors modulate the association between physical activity and colorectal cancer.

BACKGROUND: Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-PA interaction analysis. METHODS: Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. RESULTS: PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81-0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10- 8). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75-0.85), but no significant PA-CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10- 8). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72-0.82). CONCLUSIONS: In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.

GWAS↗

PubMed2025

Evaluation of Multiple Breast Cancer Polygenic Risk Score Panels in Women of Latin American Heritage.

BACKGROUND: A substantial portion of the genetic predisposition for breast cancer is explained by multiple common genetic variants of relatively small effect. A subset of these variants, which have been identified mostly in individuals of European (EUR) and Asian ancestries, have been combined to construct a polygenic risk score (PRS) to predict breast cancer risk, but the prediction accuracy of existing PRSs in Hispanic/Latinx individuals (H/L) remain relatively low. We assessed the performance of several existing PRS panels with and without addition of H/L-specific variants among self-reported H/L women. METHODS: PRS performance was evaluated using multivariable logistic regression and the area under the ROC curve. RESULTS: Both EUR and Asian PRSs performed worse in H/L samples compared with original reports. The best EUR PRS performed better than the best Asian PRS in pooled H/L samples. EUR PRSs had decreased performance with increasing Indigenous American (IA) ancestry, while Asian PRSs had increased performance with increasing IA ancestry. The addition of two H/L SNPs increased performance for all PRSs, most notably in the samples with high IA ancestry, and did not impact the performance of PRSs in individuals with lower IA ancestry. CONCLUSIONS: A single PRS that incorporates risk variants relevant to the multiple ancestral components of individuals from Latin America, instead of a set of ancestry-specific panels, could be used in clinical practice. IMPACT: The results highlight the importance of population-specific discovery and suggest a straightforward approach to integrate ancestry-specific variants into PRSs for clinical application.

Adult↗

PubMed2006

Age-related smoking progression among adolescents in China.

PURPOSE: This study examined the differences in smoking progression between middle and upper school students. METHODS: The China Seven Cities Study (CSCS) is a longitudinal cohort study. The current sample consists of subjects with both baseline and one-year follow-up measures collected between October 2002 and December 2003. There were 4842 students from 62 middle schools and 5806 students from 83 upper schools. Multilevel random-coefficient modeling techniques were applied. RESULTS: Among male never or lifetime ever smokers, middle school students were susceptible to transitioning more rapidly than upper school students (never--RR: 1.272, 95% confidence interval [CI]: .985-1.642; lifetime ever--RR: 1.497, 95% CI: .979-2.290). Among female lifetime ever smokers, middle school students were more likely to progress than upper school students (RR: 1.353, 95% CI: 1.038-1.763). CONCLUSION: This longitudinal study is the first to explore differences in smoking progression among adolescents in China. The results revealed that over a one-year interval, there was greater progression across smoking trajectories during early adolescence (corresponding to middle school) than later adolescence (upper school). This is consistent with the neurological development hypothesis, but does not rule out alternative explanations. These findings are important to consider relative to the content and timing of prevention interventions in China where smoking rates approach 70% in adult males and are increasing rapidly in women.

Adolescent↗

PubMed2006

XRCC1, XRCC3, and XPD polymorphisms as modifiers of the effect of smoking and alcohol on colorectal adenoma risk.

Using a sigmoidoscopy-based case-control study (753 cases, 799 controls) in Los Angeles County, we investigated the potential modifier role in the effect of alcohol and smoking of single-nucleotide polymorphisms (SNP) in three DNA repair genes, XRCC1 (Arg194Trp and Arg399Gln), XRCC3 (Thr241Met), and XPD (Lys751Gln). We have previously reported an inverse association between the XRCC1 codon 399 SNP and adenoma risk among these subjects. We now report that subjects with the XPD Gln/Gln genotype were inversely associated with adenoma risk [odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-1.0] when compared with subjects with the Lys/Lys and Lys/Gln genotypes combined. This association differed between different ethnic groups (gene x race heterogeneity likelihood ratio test, P = 0.009), with a stronger inverse association among Latinos (OR, 0.1; 95% CI, 0.01-0.5) than among non-Latinos (OR, 0.9; 95% CI, 0.-1.3). We found no evidence of an XRCC3 x smoking or alcohol interaction or an XRCC1 x alcohol interaction. Instead, our data supported an XRCC1 x smoking interaction (P = 0.048). Whereas XPD did not modify the effect of smoking, our data suggested an XPD x alcohol interaction. Analyses ignoring XPD showed no association between alcohol intake and adenoma prevalence; however, among carriers of the codon 751 Gln/Gln genotype, we found a significant positive association (OR, 2.5; 95% CI, 1.2-5.2 for ever drinkers; test of interaction P = 0.04). Our data suggest that the effects of smoking and alcohol may vary depending on the genetic background of proteins that participate in the base excision repair and nucleotide excision repair pathways.

Adenoma↗

PubMed2006

Interleukin-6-related genotypes, body mass index, and risk of multiple myeloma and plasmacytoma.

Interleukin-6 (IL-6) promotes normal plasma cell development and proliferation of myeloma cells in culture. We evaluated IL-6 genotypes and body mass index (BMI) in a case-control study of multiple myeloma and plasmacytoma. DNA samples and questionnaires were obtained from incident cases of multiple myeloma (n = 134) and plasmacytoma (n = 16; plasma cell neoplasms) ascertained from the Los Angeles County population-based cancer registry and from siblings or cousins of cases (family controls, n = 112) and population controls (n = 126). Genotypes evaluated included IL-6 promoter gene single nucleotide polymorphisms (SNP) at positions -174, -572, and -597; one variable number of tandem repeats (-373 A(n)T(n)); and one SNP in the IL-6 receptor (IL-6ralpha) gene at position -358. The variant allele of the IL-6 promoter SNP -572 was associated with a roughly 2-fold increased risk of plasma cell neoplasms when cases were compared with family [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 0.7-4.7] or population controls (OR, 2.4; 95% CI, 1.2-4.7). The -373 9A/9A genotype was associated with a decreased risk compared with the most common genotype (OR for cases versus family controls, 0.4; 95% CI, 0.1-1.7; OR for cases versus population controls, 0.3; 95% CI, 0.1-0.9). No other SNPs were associated with risk. Obesity (BMI >or= 30 kg/m(2)) increased risk nonsignificantly by 40% and 80% when cases were compared with family controls or population controls, respectively, relative to persons with a BMI of <25 kg/m(2). These results suggest that IL-6 promoter genotypes may be associated with increased risk of plasma cell neoplasms.

Adult↗

PubMed2005

Identifying susceptibility genes by using joint tests of association and linkage and accounting for epistasis.

Simulated Genetic Analysis Workshop 14 data were analyzed by jointly testing linkage and association and by accounting for epistasis using a candidate gene approach. Our group was unblinded to the "answers." The 48 single-nucleotide polymorphisms (SNPs) within the six disease loci were analyzed in addition to five SNPs from each of two non-disease-related loci. Affected sib-parent data was extracted from the first 10 replicates for populations Aipotu, Kaarangar, and Danacaa, and analyzed separately for each replicate. We developed a likelihood for testing association and/or linkage using data from affected sib pairs and their parents. Identical-by-descent (IBD) allele sharing between sibs was explicitly modeled using a conditional logistic regression approach and incorporating a covariate that represents expected IBD allele sharing given the genotypes of the sibs and their parents. Interactions were accounted for by performing likelihood ratio tests in stages determined by the highest order interaction term in the model. In the first stage, main effects were tested independently, and in subsequent stages, multilocus effects were tested conditional on significant marginal effects. A reduction in the number of tests performed was achieved by prescreening gene combinations with a goodness-of-fit chi square statistic that depended on mating-type frequencies. SNP-specific joint effects of linkage and association were identified for loci D1, D2, D3, and D4 in multiple replicates. The strongest effect was for SNP B03T3056, which had a median p-value of 1.98 x 10(-34). No two- or three-locus effects were found in more than one replicate.

Databases, Genetic↗

PubMed2005

A testing framework for identifying susceptibility genes in the presence of epistasis.

An efficient testing strategy called the "focused interaction testing framework" (FITF) was developed to identify susceptibility genes involved in epistatic interactions for case-control studies of candidate genes. In the FITF approach, likelihood-ratio tests are performed in stages that increase in the order of interaction considered. Joint tests of main effects and interactions are performed conditional on significant lower-order effects. A reduction in the number of tests performed is achieved by prescreening gene combinations with a goodness-of-fit chi2 statistic that depends on association among candidate genes in the pooled case-control group. Multiple testing is accounted for by controlling false-discovery rates. Simulation analysis demonstrated that the FITF approach is more powerful than marginal tests of candidate genes. FITF also outperformed multifactor dimensionality reduction when interactions involved additive, dominant, or recessive genes. In an application to asthma case-control data from the Children's Health Study, FITF identified a significant multilocus effect between the nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase gene (NQO1), myeloperoxidase gene (MPO), and catalase gene (CAT) (unadjusted P = .00026), three genes that are involved in the oxidative stress pathway. In an independent data set consisting primarily of African American and Asian American children, these three genes also showed a significant association with asthma status (P = .0008).

Black or African American↗

PubMed2005

Intercellular adhesion molecule-1 and childhood asthma.

We investigated the role of intercellular adhesion molecule-1 in childhood asthma by examining associations of functional variants at codons 29 (A --> T), 241 (G --> A), and 469 (A --> G) in Children's Health Study participants. Among African-Americans, 469G carriers had lower risk for asthma (ever asthma OR = 0.4, 95% CI 0.2-0.9) but increased risk among 29T carriers (early onset active asthma OR = 2.2, 95% CI 1.0-4.9). Protective associations with the 241A allele were observed among non-Hispanic and Hispanic whites (ever asthma OR = 0.7, 95% CI 0.6-0.9; early onset active asthma OR = 0.5, 95% CI 0.4-0.8), and these associations were not confounded by population stratification. To gauge the potential impact of confounding by population stratification, we performed analyses by ethnic group and in an independent family-based sample. Regional associations were stable across analyses. Haplotype associations of the four common haplotypes (29A/241G/469A, AGG, TGA, and AAG) with asthma showed that Hispanics with the AAG haplotype had lower asthma risk compared to carriers of two copies of AGA haplotype (OR = 0.6, 95% CI 0.4-0.9). Among non-Hispanic whites, the AAG haplotype was associated with reduced risk for active asthma. For African-Americans, who had a low frequency of the AAG haplotype, carrying one copy of the AGG haplotype was associated with a lower risk of asthma (OR = 0.3, 95% CI 0.1-0.8), as compared with two copies of the AGA haplotype. Consistent with information on variant function, the 241A and 469G variants may indicate haplotypes that are associated with reduced risk for asthma.

Adolescent↗

PubMed2005

Common genetic variation in the sex steroid hormone-binding globulin (SHBG) gene and circulating shbg levels among postmenopausal women: the Multiethnic Cohort.

SHBG transports sex steroid hormones in the blood, and levels in humans are thought to partially be genetically determined. Recently, studies have found a pentanucleotide (TAAAA)n repeat polymorphism in the promoter of the SHBG gene and a missense polymorphism in exon 6 (Asp327Asn) to predict circulating SHBG levels. Based on the potential role of common genetic variation in SHBG to serve as a marker of SHBG levels in the general population, we evaluated the association between the (TAAAA)n repeat polymorphism, Asp327Asn polymorphism, and SHBG levels in a population of African-American, Native Hawaiian, Japanese, Latina, and white healthy postmenopausal women from the Multiethnic Cohort Study (n = 372). Mean SHBG levels were not significantly different between carriers and noncarriers of the Asn327 allele [minor allele frequency range across ethnic groups, 0.02-0.14; Asp/Asn and Asn/Asn genotypes, 33.6 mol/liter; 95% confidence interval (CI), 28.2-40.0; n = 49; Asp/Asp genotype, 30.8 mol/liter (95% CI, 28.7-33.1; n = 296); P = 0.37]. For the repeat polymorphism, we observed six different SHBG repeat alleles segregating in the population (TAAAA6-11), and the distribution of these alleles varied widely across populations. We found suggestive evidence of linkage disequilibrium between the Asn327 allele and the eight-repeat allele in all populations except African-Americans (P > or = 0.08). In analysis of the repeat polymorphism, SHBG levels among carriers of two short alleles (seven or fewer repeats; 31.2 nmol/liter; 95% CI, 27.3-35.6; n = 82) were not statistically different from those of carriers of two long alleles (more than seven repeats; 32.7 nmol/liter; 95% CI, 29.4-36.3; n = 124; P = 0.59). We did, however, observe individual genotypic classes (n = 16) to contribute modestly to the overall prediction of SHBG levels (by analysis of covariance, P = 0.03). Carriers of the six-repeat allele (27.9 nmol/liter; 95% CI, 25.2-30.8; n = 147) were found to have nominally significantly lower SHBG levels than noncarriers (32.4 nmol/liter; 95% CI, 29.7-35.2; n = 202; P = 0.03). This effect was stronger among the subset of women who also carried the Asn327 allele (interaction, P = 0.006). In summary, these results suggest that genetic variation at the SHBG locus may contribute to modest differences in SHBG levels among healthy postmenopausal women, and that much larger studies will be needed to better comprehend the effects of common variations at this locus in predicting circulating SHBG levels.

Aged↗

PubMed2005

Testing association and linkage using affected-sib-parent study designs.

We have developed a method for jointly testing linkage and association using data from affected sib pairs and their parents. We specify a conditional logistic regression model with two covariates, one that quantifies association (either direct association or indirect association via linkage disequilibrium), and a second that quantifies linkage. The latter covariate is computed based on expected identity-by-descend (ibd) sharing of marker alleles between siblings. In addition to a joint test of linkage and association, our general framework can be used to obtain a linkage test comparable to the mean test (Blackwelder and Elston [1985] Genet. Epidemiol. 2:85-97), and an association test comparable to the Family-Based Association Test (FBAT; Rabinowitz and Laird [2000] Hum. Hered. 50:211-223). We present simulation results demonstrating that our joint test can be more powerful than some standard tests of linkage or association. For example, with a relative risk of 2.7 per variant allele at a disease locus, the estimated power to detect a nearby marker with a modest level of LD was 58.1% by the mean test (linkage only), 69.8% by FBAT, and 82.5% by our joint test of linkage and association. Our model can also be used to obtain tests of linkage conditional on association and association conditional on linkage, which can be helpful in fine mapping.

Alleles↗

PubMed2004

Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR.

BACKGROUND: The prostate is an androgen-regulated organ and polymorphisms in genes involved in testosterone synthesis, in particular, SRD5A2 (A49T and V89L variants), CYP17 (MspAI variant), and the AR (CAG, GGC repeats), represent candidate risk factors for prostate cancer incidence and aggressiveness. METHODS: We evaluated the relationship between these five polymorphisms and prostate cancer risk in a family-based case-control study (N = 920). Cases were diagnosed at major medical institutions in Cleveland Ohio, and Detroit Michigan, and their unaffected brothers were used as controls. Associations were investigated with regard to prostate cancer risk, and clinical characteristics at diagnosis (i.e., tumor stage/grade, age, family history). RESULTS: The SRD5A2 V89L variant was associated with an increased risk of prostate cancer (OR = 1.56, P = 0.02). This association was driven primarily by men diagnosed at an earlier age (OR = 2.35, P = 0.001), or with more aggressive disease (OR = 1.63, P = 0.06). None of the other variants exhibited noteworthy associations with disease. CONCLUSIONS: These findings suggest that the SRD5A2 V89L variant may influence risk of developing prostate cancer, especially among men with a younger age of diagnosis or more aggressive disease.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2004

Genetic dissection of complex traits with chromosome substitution strains of mice.

Chromosome substitution strains (CSSs) have been proposed as a simple and powerful way to identify quantitative trait loci (QTLs) affecting developmental, physiological, and behavioral processes. Here, we report the construction of a complete CSS panel for a vertebrate species. The CSS panel consists of 22 mouse strains, each of which carries a single chromosome substituted from a donor strain (A/J) onto a common host background (C57BL/6J). A survey of 53 traits revealed evidence for 150 QTLs affecting serum levels of sterols and amino acids, diet-induced obesity, and anxiety. These results demonstrate that CSSs greatly facilitate the detection and identification of genes that control the wide diversity of naturally occurring phenotypic variation in the A/J and C57BL/6J inbred strains.

Amino Acids↗

PubMed2004

SNPs, haplotypes, and model selection in a candidate gene region: the SIMPle analysis for multilocus data.

Modern molecular techniques make discovery of numerous single nucleotide polymorphims (SNPs) in candidate gene regions feasible. Conventional analysis relies on either independent tests with each variant or the use of haplotypes in association analysis. The first technique ignores the dependencies between SNPs. The second, though it may increase power, often introduces uncertainty by estimating haplotypes from population data. Additionally, as the number of loci expands for a haplotype, ambiguity in interpretation increases for determining the underlying genetic components driving a detected association. Here, we present a genotype-level analysis to jointly model the SNPs via a SNP interaction model with phase information (SIMPle) to capture the underlying haplotype structure. This analysis estimates both the risk associated with each variant and the importance of phase between pairwise combinations of SNPs. Thus, rather than selecting between genotype- or haplotype-level approaches, the SIMPle method frames the analysis of multilocus data in a model selection paradigm, the aim to determine which SNPs, phase terms, and linear combinations best describe the relation between genetic variation and a trait of interest. To avoid unstable estimation due to sparse data and to incorporate both the dependencies among terms and the uncertainty in model selection, we propose a Bayes model averaging procedure. This highlights key SNPs and phase terms and yields a set of best representative models. Using simulations, we demonstrate the utility of the SIMPle model to identify crucial SNPs and underlying haplotype structures across a variety of causal models and genetic architectures.

Bayes Theorem↗

PubMed2004

Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2.

Genes involved in the testosterone biosynthetic pathway - such as CYP17A1, CYP3A4, and SRD5A2 - represent strong candidates for affecting prostate cancer. Previous work has detected associations between individual variants in these three genes and prostate cancer risk and aggressiveness. To more comprehensively evaluate CYP17A1, CYP3A4, and SRD5A2, we undertook a two-phase study of the relationship between their genotypes/haplotypes and prostate cancer. Phase I of the study first searched for single-nucleotide polymorphisms (SNPs) in these genes by resequencing 24 individuals from the Coriell Polymorphism Discovery Resource, 92-110 men from prostate cancer case-control sibships, and by leveraging public databases. In all, 87 SNPs were discovered and genotyped in 276 men from case-control sibships. Those SNPs exhibiting preliminary case-control allele frequency differences, or distinguishing (ie, 'tagging') common haplotypes across the genes, were identified for further study (24 SNPs in total). In Phase II of the study, the 24 SNPs were genotyped in an additional 841 men from case-control sibships. Finally, associations between genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and prostate cancer were evaluated in the total case-control sample of 1117 brothers from 506 sibships. Family-based analyses detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (P-values between 0.006 and 0.05), a CYP3A4 haplotype (P-values 0.05 and 0.009 in nonstratified and stratified analysis, respectively), and two SRD5A2 SNPs in strong linkage disequilibrium (P=0.02). Undertaking a two-phase study comprising SNP discovery, haplotype tagging, and association analyses allowed us to more fully decipher the relation between CYP17A1, CYP3A4, and SRD5A2 and prostate cancer.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2004

Commentary: the concept of 'Mendelian Randomization'.

Explore the source record for details and available documents.

Bias↗

PubMed2004

DNA repair gene XRCC1 and XPD polymorphisms and risk of prostate cancer.

The X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD) genes are involved in base excision repair and nucleotide excision repair of DNA repair pathways, respectively. A growing body of evidence suggests that XRCC1 and XPD are important in environmentally induced cancers, and polymorphisms in both genes have been identified. To determine whether the XRCC1 (codon Arg399Gln) and XPD (codon Asp312Asn and codon Lys751Gln) polymorphisms are associated with prostate cancer susceptibility, we genotyped these polymorphisms in a primarily Caucasian sample of 506 sibships (n = 1,117) ascertained through a brother with prostate cancer. Sibships were analyzed with a Cox proportional hazards model with age at prostate cancer diagnosis as the outcome. Of the three polymorphisms investigated, only the XPD codon 312 Asn/Asn genotype had an odds ratio (OR) significantly different from one (OR, 1.61; 95% CI, 1.03-2.53). Analyses stratified by the clinical characteristics of affected brothers in the sibship did not reveal any significant heterogeneity in risk. In exploring two-way gene interactions, we found a markedly elevated risk for the combination of the XPD codon 312 Asn/Asn and XRCC1 codon 399 Gln/Gln genotypes (OR, 4.81; 95% CI, 1.66-13.97). In summary, our results suggest that the XPD codon 312 Asn allele may exert a modest positive effect on prostate cancer risk when two copies of the allele are present, and this effect is enhanced by the XRCC codon 399 Gln allele in its recessive state.

Aged↗

PubMed2004

Relationship between methylenetetrahydrofolate reductase C677T and A1298C genotypes and haplotypes and prostate cancer risk and aggressiveness.

Previous reports indicate that polymorphisms in the MTHFR gene play a role in cancer development, but their potential impact on prostate cancer has not been well studied. Here, we evaluate the association between two MTHFR polymorphisms, C677T and A1298C, and prostate cancer risk and aggressiveness in a moderately large family-based case-control study (439 cases and 479 sibling controls). Among all study subjects, we observed no association between the C677T variant and prostate cancer but a slight positive association between the A1298C variant and risk of this disease [odds ratio (OR) 1.41, 95% confidence interval (CI) 0.96-2.06; P = 0.08]. When stratifying the study population by disease aggressiveness at diagnosis, the C677T variant was positively associated with risk among men with less advanced disease (OR 1.86, 95% CI 1.00-3.46; P = 0.05). In contrast, when looking at men with more advanced disease, the C677T variant was inversely associated with risk (OR 0.51, 95% CI 0.32-0.82; P = 0.01), whereas the A1298C variant was positively associated with risk (OR 1.79, 95% CI 1.06-3.02; P = 0.03). Furthermore, the 677T-1298A haplotype was positively associated with prostate cancer among men with less advanced disease (OR 1.84, 95% CI 1.07-3.16; P = 0.03) and inversely associated with risk of more advanced disease (OR 0.47, 95% CI 0.29-0.76; P = 0.002). Our findings suggest that 677T and 1298A, or another variant on their haplotype, may be associated with a reduced risk of progression to more advanced prostate cancer.

Adult↗

PubMed2003

Comparison of missing data approaches in linkage analysis.

BACKGROUND: Observational cohort studies have been little used in linkage analyses due to their general lack of large, disease-specific pedigrees. Nevertheless, the longitudinal nature of such studies makes them potentially valuable for assessing the linkage between genotypes and temporal trends in phenotypes. The repeated phenotype measures in cohort studies (i.e., across time), however, can have extensive missing information. Existing methods for handling missing data in observational studies may decrease efficiency, introduce biases, and give spurious results. The impact of such methods when undertaking linkage analysis of cohort studies is unclear. Therefore, we compare here six methods of imputing missing repeated phenotypes on results from genome-wide linkage analyses of four quantitative traits from the Framingham Heart Study cohort. RESULTS: We found that simply deleting observations with missing values gave many more nominally statistically significant linkages than the other five approaches. Among the latter, those with similar underlying methodology (i.e., imputation- versus model-based) gave the most consistent results, although some discrepancies remained. CONCLUSION: Different methods for addressing missing values in linkage analyses of cohort studies can give substantially diverse results, and must be carefully considered to protect against biases and spurious findings.

Algorithms↗