Methodological Issues in Multistage Genome-Wide Association Studies

Because of the high cost of commercial genotyping chip technologies, many investigations have used a two-stage design for genome-wide association studies, using part of the sample for an initial discovery of ``promising'' SNPs at a less stringent significance level and the remainder in a joint analysis of just these SNPs using custom genotyping. Typical cost savings of about 50% are possible with this design to obtain comparable levels of overall type I error and power by using about half the sample for stage I and carrying about 0.1% of SNPs forward to the second stage, the optimal design depending primarily upon the ratio of costs per genotype for stages I and II. However, with the rapidly declining costs of the commercial panels, the generally low observed ORs of current studies, and many studies aiming to test multiple hypotheses and multiple endpoints, many investigators are abandoning the two-stage design in favor of simply genotyping all available subjects using a standard high-density panel. Concern is sometimes raised about the absence of a ``replication'' panel in this approach, as required by some high-profile journals, but it must be appreciated that the two-stage design is not a discovery/replication design but simply a more efficient design for discovery using a joint analysis of the data from both stages. Once a subset of highly-significant associations has been discovered, a truly independent ``exact replication'' study is needed in a similar population of the same promising SNPs using similar methods.Comment: Published in at http://dx.doi.org/10.1214/09-STS288 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Monoid presentations of groups by finite special string-rewriting systems

We show that the class of groups which have monoid presentations by means of finite special [λ]-confluent string-rewriting systems strictly contains the class of plain groups (the groups which are free products of a finitely generated free group and finitely many finite groups), and that any group which has an infinite cyclic central subgroup can be presented by such a string-rewriting system if and only if it is the direct product of an infinite cyclic group and a finite cyclic group

Multiple imputation methods for longitudinal blood pressure measurements from the Framingham Heart Study

Missing data are a great concern in longitudinal studies, because few subjects will have complete data and missingness could be an indicator of an adverse outcome. Analyses that exclude potentially informative observations due to missing data can be inefficient or biased. To assess the extent of these problems in the context of genetic analyses, we compared case-wise deletion to two multiple imputation methods available in the popular SAS package, the propensity score and regression methods. For both the real and simulated data sets, the propensity score and regression methods produced results similar to case-wise deletion. However, for the simulated data, the estimates of heritability for case-wise deletion and the two multiple imputation methods were much lower than for the complete data. This suggests that if missingness patterns are correlated within families, then imputation methods that do not allow this correlation can yield biased results

Adolescent Reproductive Knowledge, Attitudes, and Beliefs and Future Fatherhood.

PurposeWith a growing focus on the importance of men's reproductive health, including preconception health, the ways in which young men's knowledge, attitudes, and beliefs (KAB) predict their reproductive paths are understudied. To determine if reproductive KAB predicts fatherhood status, timing and residency (living with child or not).MethodsReproductive KAB and fatherhood outcomes were analyzed from the National Longitudinal Study of Adolescent Health, a 20-year, nationally representative study of individuals from adolescence into adulthood. Four measures of reproductive KAB were assessed during adolescence in waves I and II. A generalized linear latent and mixed model predicted future fatherhood status (nonfather, resident/nonresident father, adolescent father) and timing while controlling for other socio-demographic variables.ResultsOf the 10,253 men, 3,425 were fathers (686 nonresident/2,739 resident) by wave IV. Higher risky sexual behavior scores significantly increased the odds of becoming nonresident father (odds ratio [OR], 1.30; p < .0001), resident father (OR, 1.07; p = .007), and adolescent father (OR, 1.71; p < .0001); higher pregnancy attitudes scores significantly increased the odds of becoming a nonresident father (OR, 1.20; p < .0001) and resident father (OR, 1.11; p < .0001); higher birth control self-efficacy scores significantly decreased the odds of becoming a nonresident father (OR, .72; p < .0001) and adolescent father (OR, .56; p = .01).ConclusionsYoung men's KAB in adolescence predicts their future fatherhood and residency status. Strategies that address adolescent males' reproductive KAB are needed in the prevention of unintended reproductive consequences such as early and nonresident fatherhood

Longitudinal Study of Body Mass Index in Young Males and the Transition to Fatherhood.

Despite a growing understanding that the social determinants of health have an impact on body mass index (BMI), the role of fatherhood on young men's BMI is understudied. This longitudinal study examines BMI in young men over time as they transition from adolescence into fatherhood in a nationally representative sample. Data from all four waves of the National Longitudinal Study of Adolescent Health supported a 20-year longitudinal analysis of 10,253 men beginning in 1994. A "fatherhood-year" data set was created and changes in BMI were examined based on fatherhood status (nonfather, nonresident father, resident father), fatherhood years, and covariates. Though age is positively associated with BMI over all years for all men, comparing nonresident and resident fathers with nonfathers reveals different trajectories based on fatherhood status. Entrance into fatherhood is associated with an increase in BMI trajectory for both nonresident and resident fathers, while nonfathers exhibit a decrease over the same period. In this longitudinal, population-based study, fatherhood and residence status play a role in men's BMI. Designing obesity prevention interventions for young men that begin in adolescence and carry through young adulthood should target the distinctive needs of these populations, potentially improving their health outcomes

Segregation and linkage analysis for longitudinal measurements of a quantitative trait

We present a method for using slopes and intercepts from a linear regression of a quantitative trait as outcomes in segregation and linkage analyses. We apply the method to the analysis of longitudinal systolic blood pressure (SBP) data from the Framingham Heart Study. A first-stage linear model was fit to each subject's SBP measurements to estimate both their slope over time and an intercept, the latter scaled to represent the mean SBP at the average observed age (53.7 years). The subject-specific intercepts and slopes were then analyzed using segregation and linkage analysis. We describe a method for using the standard errors of the first-stage intercepts and slopes as weights in the genetic analyses. For the intercepts, we found significant evidence of a Mendelian gene in segregation analysis and suggestive linkage results (with LOD scores ≥ 1.5) for specific markers on chromosomes 1, 3, 5, 9, 10, and 17. For the slopes, however, the data did not support a Mendelian model, and thus no formal linkage analyses were conducted

The trimeric organisation of photosystem I is not necessary for the iron-stress induced CP43′ protein to functionally associate with this reaction centre

AbstractA mutant of Synechocystis PCC 6803 lacking the PsaL subunit of photosystem I (PSI) has been grown in iron-deficient media to induce the expression of the isiA gene, which encodes the chlorophyll a-binding protein CP43′. The purpose of this was to establish whether or not the formation of an 18-mer CP43′-PSI supercomplex reported for wild type Synechocystis cells [Nature 412 (2001) 743–745] was dependent on the trimeric conformation of the cyanobacterial PSI reaction centre. Structural characterisation by electron microscopy and single particle image analysis has revealed that the PsaL-mutant does not form trimers of PSI. However, despite this, CP43′ was found to associate with the PSI monomer. The PSI monomer bound six or seven copies of CP43′ along one edge of the PSI monomer and can be compared with one segment of the trimeric 18-mer CP43′-PSI supercomplex. We therefore conclude that the trimeric nature of cyanobacterial PSI is not required for the assembly of the CP43′ antenna system under iron-deficient conditions

Demographic variation and habitat specialization of tree species in a diverse tropical forest of Cameroon

Background: Many tree species in tropical forests have distributions tracking local ridge-slope-valley topography. Previous work in a 50-ha plot in Korup National Park, Cameroon, demonstrated that 272 species, or 63% of those tested, were significantly associated with topography. Methods: We used two censuses of 329,000 trees ≥1 cm dbh to examine demographic variation at this site that would account for those observed habitat preferences. We tested two predictions. First, within a given topographic habitat, species specializing on that habitat (‘residents’) should outperform species that are specialists of other habitats (‘foreigners’). Second, across different topographic habitats, species should perform best in the habitat on which they specialize (‘home’) compared to other habitats (‘away’). Species’ performance was estimated using growth and mortality rates. Results: In hierarchical models with species identity as a random effect, we found no evidence of a demographic advantage to resident species. Indeed, growth rates were most often higher for foreign species. Similarly, comparisons of species on their home vs. away habitats revealed no sign of a performance advantage on the home habitat. Conclusions: We reject the hypothesis that species distributions along a ridge-valley catena at Korup are caused by species differences in trees ≥1 cm dbh. Since there must be a demographic cause for habitat specialization, we offer three alternatives. First, the demographic advantage specialists have at home occurs at the reproductive or seedling stage, in sizes smaller than we census in the forest plot. Second, species may have higher performance on their preferred habitat when density is low, but when population builds up, there are negative density-dependent feedbacks that reduce performance. Third, demographic filtering may be produced by extreme environmental conditions that we did not observe during the census interval

Quantifying the Origin and Distribution of Intracluster Light in a Fornax-like Cluster

Using a cosmological $N$-body simulation, we investigate the origin and distribution of stars in the intracluster light (ICL) of a Fornax-like cluster. In a dark matter only simulation we identify a halo which, at $z=0$, has $M_200 \simeq 4.1 \times 10^{13}M_{sun}$ and $r_{200} = 700kpc$, and replace infalling subhalos with models that include spheroid and disc components. As they fall into the cluster, the stars in some of these galaxies are stripped from their hosts, and form the ICL. We consider the separate contributions to the ICL from stars which originate in the haloes and the discs of the galaxies. We find that disc ICL stars are more centrally concentrated than halo ICL stars. The majority of the disc ICL stars are associated with one initially disc-dominated galaxy that falls to the centre of the cluster and is heavily disrupted, producing part of the cD galaxy. At radial distances greater than 200kpc, well beyond the stellar envelope of the cD galaxy, stars formerly from the stellar haloes of galaxies dominate the ICL. Therefore at large distances, the ICL population is dominated by older stars.Comment: Paper published as MNRAS , 2017, 467, 4501 This version corrects a small typo in the authors fiel