Power estimation for non-standardized multisite studies

AbstractA concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions

Proceedings of the Fourth Caldwell Conference, St. Catherines Island, Georgia, March 27-29, 2009.

391 p. : ill. (chiefly col.), maps (chiefly col.) ; 26 cm. "Issued March 23, 2011."This edited volume addresses the geoarchaeology of St. Catherines Island (Georgia). The field of geoarchaeology has typically been defined as either geology pursued within an archaeological framework or (sometimes the reverse) as archaeology framed with the help of geological methodology. Either way, the formalized objectives of geoarchaeology define a broad range of pursuits, from placing archaeological sites into relative and absolute temporal context through the application of stratigraphic principles and absolute dating techniques, to understanding the natural processes of site formation, to reconstructing the landscapes that existed around a site or group of sites at the time of occupation. The editors of this volume have generally followed the lead of G.R. Rapp and C.L. Hill (2006, Geoarchaeology : the earth-science approach to archaeological interpretation) by stressing the importance of multiple viewpoints and methodologies in applying geoscience techniques to evaluate the archaeological record. In the broadest sense, then, Geoarchaeology of St. Catherines Island applies multiple earth science concepts, techniques, or knowledge bases to the known archaeological record and the processes that created that record. This volume consists of 16 papers presenting the newest research on the stratigraphic and geomorphological evolution of the St. Catherines Island landscape. Of particular interest are presentations addressing the relative timing and nature of sedimentation, paleobiology, sea level change, stream capture, hydrology, and erosional patterning evident on St. Catherines Island (and to some degree the rest of the Georgia Bight). These papers were initially presented at the Fourth Caldwell Conference, cosponsored by the American Museum of Natural History and the St. Catherines Island Foundation, held on St. Catherines Island (Georgia), March 27-29, 2009. Table of contents: Why this archaeologist cares about geoarchaeology : some pasts and futures of St. Catherines Island / David Hurst Thomas -- Evolution of late Pleistocene-Holocene climates and environments of St. Catherines Island and the Georgia Bight / Fredrick J. Rich, Anthony Vega, and Frank J. Vento -- Geoarchaeological research at St. Catherines Island : defining the geological foundation / Gale A. Bishop, Brian K. Meyer, R. Kelly Vance, and Fredrick J. Rich -- Development of a late Pleistocene-Holocene genetic stratigraphic framework for St. Catherines Island : archaeological implications / Frank J. Vento and Patty A. Stahlman -- Ichnological diagnosis of ancient storm-washover fans, Yellow Banks Bluff, St. Catherines Island / Anthony J. Martin and Andrew K. Rindsberg -- Quaternary vegetation and depositional history of St. Catherines Island / Fredrick J. Rich and Robert K. Booth -- Recent shoreline erosion and vertical accretion patterns, St. Catherines Island / Donald B. Potter Jr. -- Role of storm events in beach ridge formation, St. Catherines Island / Harold B. Rollins, Kathi Beratan, and James E. Pottinger -- Drainage changes at Ossabaw, St. Catherines, and Sapelo sounds and their influence on island morphology and spit building on St. Catherines Island / Timothy M. Chowns -- Vibracores and vibracore transects : constraining the geological and cultural history of St. Catherines Island / Gale A. Bishop, David Hurst Thomas, Matthew C. Sanger, Brian K. Meyer, R. Kelly Vance, Robert K. Booth, Fredrick J. Rich, Donald B. Potter, and Timothy Keith-Lucas -- Application of ground penetrating radar to investigations of the stratigraphy, structure, and hydrology of St. Catherines Island / R. Kelly Vance, Gale A. Bishop, Fredrick J. Rich, Brian K. Meyer, and Eleanor J. Camann -- Postsettlement dispersal and dynamic repopulation of estuarine habitats by adult Mercenaria mercenaria, St. Catherines Island / Robert S. Prezant, Harold B. Rollins, and Ronald B. Toll -- The foundation for sea turtle geoarchaeology and zooarchaeology : morphology of recent and ancient sea turtle nests, St. Catherines Island, Georgia, and Cretaceous Fox Hills Sandstone, Elbert County, Colorado / Gale A. Bishop, Fredric L. Pirkle, Brian K. Meyer, and William A. Pirkle -- Sea turtle habitat deterioration on St. Catherines Island : defining the modern transgression / Gale A. Bishop and Brian K. Meyer -- Modeling indigenous hunting and harvesting of sea turtles and their eggs on the Georgia Coast / Gale A. Bishop, David Hurst Thomas, and Brian K. Meyer -- Geomorphology, sea level, and marine resources : St. Catherines Island / Harold B. Rollins and David Hurst Thomas -- Appendix 1. Noncultural radiocarbon record from St. Catherines Island : a compendium -- Appendix 2. Vibracore record from St. Catherines Island : a compendium.Conference sponsored by the American Museum of Natural History and the St. Catherines Island Foundation

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07