Prognostic gene expression signature for high-grade serous ovarian cancer.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

HLA haplotypes in primary sclerosing cholangitis patients of admixed and non-European ancestry.

Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status.

We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2, and RAD51C in a large well-annotated patient set. We evaluated EOC patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies.

Responding to biological incidents--what are the current issues in remediation of the contaminated environment?

Since 2000 there have been a number of biological incidents resulting in environmental contamination with Bacillus anthracis, the causative agent of anthrax. These incidents include the US anthrax attacks in 2001, the US and UK drumming incidents in 2006-2008 and more recently, anthrax contamination of heroin in 2009/2010 and 2012/2013. Remediation techniques used to return environments to normal have varied between incidents, with different decontamination technologies being employed. Many factors need to be considered before a remediation strategy or recovery option can be implemented, including; cost, time (length of application), public perception of risk, and sampling strategies (and results) to name a few. These incidents have demonstrated that consolidated guidance for remediating biologically contaminated environments in the aftermath of a biological incident was required. The UK Recovery Handbook for Biological Incidents (UKRHBI) is a project led by Public Health England (PHE), formerly the Health Protection Agency (HPA) to provide guidance and advice on how to remediate the environment following a biological incident or outbreak of infection, and is expected to be published in 2015.

Emerging understanding of the ΔI=1/2 rule from lattice QCD.

There has been much speculation as to the origin of the ΔI=1/2 rule (ReA0/ReA2≃22.5). We find that the two dominant contributions to the ΔI=3/2, K→ππ correlation functions have opposite signs, leading to a significant cancelation. This partial cancelation occurs in our computation of ReA2 with physical quark masses and kinematics (where we reproduce the experimental value of A2) and also for heavier pions at threshold. For ReA0, although we do not have results at physical kinematics, we do have results for pions at zero momentum with mπ≃420 MeV [ReA0/ReA2=9.1(2.1)] and mπ≃330 MeV [ReA0/ReA2=12.0(1.7)]. The contributions which partially cancel in ReA2 are also the largest ones in ReA0, but now they have the same sign and so enhance this amplitude. The emerging explanation of the ΔI=1/2 rule is a combination of the perturbative running to scales of O(2 GeV), a relative suppression of ReA2 through the cancelation of the two dominant contributions, and the corresponding enhancement of ReA0. QCD and electroweak penguin operators make only very small contributions at such scales.

K→(ππ)(I=2) decay amplitude from lattice QCD.

We report on the first realistic ab initio calculation of a hadronic weak decay, that of the amplitude A(2) for a kaon to decay into two π mesons with isospin 2. We find ReA(2)=(1.436±0.063(stat)±0.258(syst))10(-8) GeV in good agreement with the experimental result and for the hitherto unknown imaginary part we find ImA(2)=-(6.83±0.51(stat)±1.30(syst))10(-13) GeV. Moreover combining our result for ImA(2) with experimental values of ReA(2), ReA(0), and ε'/ε, we obtain the following value for the unknown ratio ImA(0)/ReA(0) within the standard model: ImA(0)/ReA(0)=-1.63(19)(stat)(20(syst)×10(-4). One consequence of these results is that the contribution from ImA(2) to the direct CP violation parameter ε' (the so-called Electroweak Penguin contribution) is Re(ε'/ε)(EWP)=-(6.52±0.49(stat)±1.24(syst))×10(-4). We explain why this calculation of A(2) represents a major milestone for lattice QCD and discuss the exciting prospects for a full quantitative understanding of CP violation in kaon decays.

The Hammersmith colorectal foot pedal.

AIM: This technical note describes use of a footpedal to switch on a rigid sigmoidoscope/proctoscope, demonstrating increased speed and efficiency of proctoscopy examination. METHOD: Use of a footpedal to control the light source of a rigid sigmoidoscope/proctoscope, enabling the user to switch the light source on and off with their foot, rather then at the wall, switch, leaving hands free. RESULTS: Benefits include increased efficiency and speed of examination with reduced time on the couch for the patient and reduced risk of the halogen lighting bulb being left switched on, thus prolonging the life of the equipment. CONCLUSION: Although we do not claim originality for its use we have found it particularly helpful and believe that its use should be more widely publicised.

Variation in genes required for normal mitosis and risk of breast cancer.

The down-regulation of genes involved in normal cell division can cause aberrant mitoses and increased cell death. Surviving cells exhibit aneuploidy and/or polyploidy. Since mitotic disruption has been linked with tumor development and progression, alterations in the expression or activity of these mitotic regulators may contribute to breast tumor formation. We evaluated associations between common inherited variation in these genes and breast cancer risk. Two hundred and five tagging and candidate functional single nucleotide polymorphisms in 30 genes required for normal cell division were genotyped in 798 breast cancer cases and 843 controls from the Mayo Clinic breast cancer study. Two variants in EIF3A (rs10787899 and rs3824830; P < 0.01) and four variants in SART1 (rs660118, rs679581, rs754532, and rs735942; P(trend) < or = 0.02) were significantly associated with an altered risk of breast cancer along with single variants in RRM2, PSCD3, C11orf51, CDC16, SNW1, MFAP1, and CDC2 (P < 0.05). Variation in both SART1 (P = 0.009) and EIF3A (P = 0.02) was also significant at the gene level. Analyses suggested that SART1 SNPs rs660118 and rs679581 accounted for the majority of the association of that gene with breast cancer. The observed associations between breast cancer risk and genetic variation in the SART1 and EIF3A genes that are required for maintenance of normal mitosis suggest a direct role for these genes in the development of breast cancer.

Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis.

BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. METHODS: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n=829) and ovarian cancer-free controls (n=941) were genotyped using an Illumina assay. RESULTS: Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR(BB vs AA) 2.81 (1.29-6.09), P=0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [OR(BB vs AA) 1.59 (1.08-2.34), P=0.02]. No other SNP associations remained suggestive in the replication populations. CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis.

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

Polymorphic variation in hOGG1 and risk of cancer: a review of the functional and epidemiologic literature.

The gene encoding human 8-oxoguanine glycosylase 1 (hOGG1) is involved in DNA base excision repair. The encoded DNA glycosylase excises 7,8-dihydro-8-oxoguanine (8-OHdG), a highly mutagenic base produced in DNA as a result of exposure to reactive oxygen species (ROS). Polymorphisms in this gene may alter glycosylase function and an individual's ability to repair damaged DNA, possibly resulting in genetic instability that can foster carcinogenesis. In order to elucidate the possible impact of polymorphisms in hOGG1, we performed a literature review of both functional and epidemiologic studies that assessed the effects of these polymorphisms on repair function, levels of oxidative DNA damage, or associations with cancer risk. Fourteen functional studies and 19 epidemiologic studies of breast, colon, esophageal, head and neck, lung, nasopharyngeal, orolaryngeal, prostate, squamous cell carcinoma of the head and neck (SCCHN), and stomach cancers were identified. Although the larger functional studies suggest reduced repair function with variant alleles in hOGG1, the evidence is generally inconclusive. There is some epidemiologic evidence that risk for esophageal, lung, nasopharyngeal, orolaryngeal, and prostate is related to hOGG1 genotype, whereas risk of breast cancer does not appear related. In studies that explored potential interactions with environmental factors, cancer risk for hOGG1 genotypes differed depending on exposure, especially for colon cancer. In summary, there is limited evidence that polymorphisms in hOGG1 affect repair function and carcinogenesis. Larger, well-designed functional and epidemiologic studies are needed to clarify these relationships, especially with respect to interactions with other DNA repair enzymes and interactions with environmental factors that increase carcinogenic load.

Familial correlations, segregation analysis, and nongenetic correlates of soy isoflavone-metabolizing phenotypes.

Particular intestinal bacteria metabolize the soy isoflavone daidzein to equol and O-desmethylangolensin (O-DMA), metabolites that can be identified in urine. Individuals that harbor bacteria capable of producing equol or O-DMA are known as equol producers (approximately 30%-50% of the population) and O-DMA producers (approximately 80%-90% of the population), respectively. The equol-producer phenotype has been associated with sex hormone-related outcomes in several studies. However, the bacteria responsible for these phenotypes have not yet been identified and factors that influence the manifestation of these phenotypes are not well understood. To evaluate familial clustering of and nongenetic factors associated with these phenotypes, 410 individuals from 112 families participated in phenotyping (3-day soy challenge and Day 4 spot urine collection). In segregation analyses of the equol-producer phenotype, the Mendelian dominant model provided the most parsimonious fit to the data, suggesting that the pattern of inheritance of the equol-producer phenotype is consistent with an autosomal dominant trait. This phenotype was positively associated with education (p trend = 0.01), but not with sex, smoking, or several dietary factors. Results of the segregation analyses of the O-DMA-producer phenotype were inconclusive; no other models provided a more parsimonious fit to the data than the general model. This phenotype was inversely associated with age in a nonlinear model (p = 0.01), positively associated with age- and sex-adjusted height (odds ratio [OR] 10-cm increase = 0.38, 95% confidence interval [CI] = 0.15, 0.95) and body mass index (kg/m(2)) (OR = 0.91, 95% CI = 0.85, 0.96), but not with sex, education, smoking, or several dietary factors. These results suggest the equol-producer phenotype may be under some degree of genetic control and that there are likely other environmental factors not evaluated in the present analysis that contribute to both of these phenotypes. These results provide a foundation for further work to refine our understanding of heritable and environmental determinants of daidzein-metabolizing phenotypes.

Clinical characteristics of prostate cancer in an analysis of linkage to four putative susceptibility loci.

PURPOSE: Hereditary prostate cancer is an etiologically heterogeneous disease with six susceptibility loci mapped to date. We aimed to describe a collection of high-risk prostate cancer families and assess linkage to multiple markers at four loci: HPC1 (1q24-25), PCaP (1q42.2-43), HPCX (Xq27-28), and CAPB (1p36). EXPERIMENTAL DESIGN: Medical record data on 505 affected men in 149 multiply-affected prostate cancer families were reviewed, and correlations of clinical traits within each family were calculated. Logarithm of odds (LOD) score and nonparametric (NPL) linkage analyses were performed; white families were stratified by age of diagnosis, grade and stage of disease, and evidence of linkage to the other loci to increase genetic homogeneity. RESULTS: Age at diagnosis was the most correlated clinical trait within families. A maximum NPL score of 2.61 (P = 0.007) appeared to confirm HPC1 linkage for families that had a prevalence of high-grade or advanced-stage prostate cancer and which were not likely to be linked to PCaP, HPCX, or CAPB. Because the NPL scores improved when families more likely to be linked to the other loci were excluded, HPC1 may act independently of the other loci. The relationship of HPC1 and aggressive disease was strongest in families with median age at diagnosis > or =65 years (NPL, 3.48; P = 0.0008). CONCLUSIONS: The current results suggest that HPC1 linkage may be most common among families with more severe prostate cancer. Stratification by clinical characteristics may be a useful tool in prostate cancer linkage analyses and may increase our understanding of hereditary prostate cancer.

Early elevation of soluble CD14 may help identify trauma patients at high risk for infection.

BACKGROUND: Elevated levels of soluble CD14 (sCD14) have been implicated in both gram-positive and gram-negative sepsis, and it has been associated with high mortality in trauma patients who become infected. METHODS: Eleven healthy volunteers and 25 adult trauma patients with multiple injuries and a mean Injury Severity Score of 32 participated. Whole blood was obtained at intervals. Immunohistochemistry was used to quantify membrane CD14 (mCD14), by flow cytometry and plasma levels of sCD14 by enzyme-linked immunosorbent assay. Analysis of variance and Student's T test with Mann-Whitney posttest were used to determine significance at p < 0.05. RESULTS: On posttrauma day 1, sCD14 was significantly different in the plasma of infected patients compared with normal controls (7.16 +/- 1.87 microg/mL vs. 4.4 +/- 0.92 microg/mL, p < 0.01), but not significantly different from noninfected patients. The percentage of monocytes expressing mCD14 in trauma patients did not differentiate them from normal controls; however, mCD14 receptor density did demonstrate significance in septic trauma patients (n = 15) versus normal controls on posttrauma day 3 (p = 0.0065). CONCLUSION: On the basis of our data, mCD14 did not differentiate infected and noninfected trauma patients, although trauma in general reduced mCD14 and elevated sCD14. Interestingly, 100% of patients who exceeded plasma levels of 8 microg/mL of sCD14 on day 1 after injury developed infections. Therefore, early high expressers of sCD14 may be at higher risk for infectious complications after trauma.

Genetic linkage analysis of prostate cancer families to Xq27-28.

OBJECTIVES: A recent linkage analysis of 360 families at high risk for prostate cancer identified the q27-28 region on chromosome X as the potential location of a gene involved in prostate cancer susceptibility. Here we report on linkage analysis at this putative HPCX locus in an independent set of 186 prostate cancer families participating in the Prostate Cancer Genetic Research Study (PROGRESS). METHODS: DNA samples from these families were genotyped at 8 polymorphic markers spanning 14.3 cM of the HPCX region. RESULTS: Two-point parametric analysis of the total data set resulted in positive lod scores at only two markers, DXS984 and DXS1193, with scores of 0.628 at a recombination fraction (theta) of 0.36 and 0.012 at theta = 0.48, respectively. The stratification of pedigrees according to the assumed mode of transmission increased the evidence of linkage at DXS984 in 81 families with no evidence of male-to-male transmission (lod = 1.062 at theta = 0.28). CONCLUSIONS: Although this analysis did not show statistically significant evidence for the linkage of prostate cancer susceptibility to Xq27-28, the results are consistent with a small percentage of families being linked to this region. The analysis further highlights difficulties in replicating linkage results in an etiologically heterogeneous, complexly inherited disease.

A genomic scan of families with prostate cancer identifies multiple regions of interest.

A 10-cM genomewide scan of 94 families with hereditary prostate cancer, including 432 affected men, was used to identify regions of putative prostate cancer-susceptibility loci. There was an average of 3.6 affected, genotyped men per family, and an overall mean age at diagnosis of 65.4 years. A total of 50 families were classified as early onset (mean age at diagnosis <66 years), and 44 families were classified as later onset (mean age at diagnosis > or =66 years). When the entire data set is considered, regions of interest (LOD score > or =1.5) were identified on chromosomes 10, 12, and 14, with a dominant model of inheritance. Under a recessive model LOD scores > or =1.5 were found on chromosomes 1, 8, 10, and 16. Stratification by age at diagnosis highlighted a putative susceptibility locus on chromosome 11, among the later-onset families, with a LOD score of 3. 02 (recombination fraction 0) at marker ATA34E08. Overall, this genomic scan suggests that there are multiple prostate cancer loci responsible for the hereditary form of this common and complex disease and that stratification by a variety of factors will be required for identification of all relevant genes.

Linkage analysis of 150 high-risk prostate cancer families at 1q24-25.

Confirmation of linkage and estimation of the proportion of families who are linked in large independent datasets is essential to understanding the significance of cancer susceptibility genes. We report here on an analysis of 150 high-risk prostate cancer families (2,176 individuals) for potential linkage to the HPC1 prostate cancer susceptibility locus at 1q24-25. This dataset includes 640 affected men with an average age at prostate cancer diagnosis of 66. 8 years (range, 39-94), representing the largest collection of high-risk families analyzed for linkage in this region to date. Linkage to multiple 1q24-25 markers was strongly rejected for the sample as a whole (lod scores at theta = 0 ranged from -30.83 to -18. 42). Assuming heterogeneity, the estimated proportion of families linked (alpha) at HPC1 in the entire dataset was 2.6%, using multipoint analysis. Because locus heterogeneity may lead to false rejection of linkage, data were stratified based on homogeneous subsets. When restricted to 21 Caucasian families with five or more affected family members and mean age at diagnosis < = 65 years, the lod scores at theta = 0 remained less than -4.0. These results indicate that the overall portion of hereditary prostate cancer families whose disease is due to inherited variation in HPC1 may be less than originally estimated.

Impact of family structure on the power of linkage tests using sib-pair methods.

This analysis sought to determine the impact of specific ascertainment criteria based upon nuclear family affectation structures. Specifically, we evaluated the predicted and observed proportion of alleles shared identical by descent conditional on the number of affected and unaffected siblings in a pedigree, and compared sib-pair method linkage results under two ascertainment schemes, random vs. selected ascertainment, for this simulated complex genetic disease. These results suggest that samples differing in the composition of affected and unaffected siblings in the family will differ in their power to detect linkage. An effect of sampling scheme on power to map using affected-sib-pair methods should be considered when a reported linkage is not found in another study population.