Functional data analysis approaches for genotype-phenotype association studies from next-generation sequencing

Next-generation DNA sequencing platforms can effectively detect the entire spectrum of genomic variation and is emerging to be a major tool for systematic exploration of the universe of variants and interactions in the entire genome. However, the data produced by next-generation sequencing technologies will suffer from three basic problems: sequence errors, assembly errors, and missing data. Current statistical methods for genetic analysis are well suited for detecting the association of common variants, but are less suitable to rare variants. This raises great challenge for sequence-based genetic studies of complex diseases.^ This research dissertation utilized genome continuum model as a general principle, and stochastic calculus and functional data analysis as tools for developing novel and powerful statistical methods for next generation of association studies of both qualitative and quantitative traits in the context of sequencing data, which finally lead to shifting the paradigm of association analysis from the current locus-by-locus analysis to collectively analyzing genome regions.^ In this project, the functional principal component (FPC) methods coupled with high-dimensional data reduction techniques will be used to develop novel and powerful methods for testing the associations of the entire spectrum of genetic variation within a segment of genome or a gene regardless of whether the variants are common or rare.^ The classical quantitative genetics suffer from high type I error rates and low power for rare variants. To overcome these limitations for resequencing data, this project used functional linear models with scalar response to develop statistics for identifying quantitative trait loci (QTLs) for both common and rare variants. To illustrate their applications, the functional linear models were applied to five quantitative traits in Framingham heart studies. ^ This project proposed a novel concept of gene-gene co-association in which a gene or a genomic region is taken as a unit of association analysis and used stochastic calculus to develop a unified framework for testing the association of multiple genes or genomic regions for both common and rare alleles. The proposed methods were applied to gene-gene co-association analysis of psoriasis in two independent GWAS datasets which led to discovery of networks significantly associated with psoriasis.^

A simulation study using the hybrid statistic and the meta-analysis t-test for data with matched and unmatched subjects in the interim analysis of clinical trials

An interim analysis is usually applied in later phase II or phase III trials to find convincing evidence of a significant treatment difference that may lead to trial termination at an earlier point than planned at the beginning. This can result in the saving of patient resources and shortening of drug development and approval time. In addition, ethics and economics are also the reasons to stop a trial earlier. In clinical trials of eyes, ears, knees, arms, kidneys, lungs, and other clustered treatments, data may include distribution-free random variables with matched and unmatched subjects in one study. It is important to properly include both subjects in the interim and the final analyses so that the maximum efficiency of statistical and clinical inferences can be obtained at different stages of the trials. So far, no publication has applied a statistical method for distribution-free data with matched and unmatched subjects in the interim analysis of clinical trials. In this simulation study, the hybrid statistic was used to estimate the empirical powers and the empirical type I errors among the simulated datasets with different sample sizes, different effect sizes, different correlation coefficients for matched pairs, and different data distributions, respectively, in the interim and final analysis with 4 different group sequential methods. Empirical powers and empirical type I errors were also compared to those estimated by using the meta-analysis t-test among the same simulated datasets. Results from this simulation study show that, compared to the meta-analysis t-test commonly used for data with normally distributed observations, the hybrid statistic has a greater power for data observed from normally, log-normally, and multinomially distributed random variables with matched and unmatched subjects and with outliers. Powers rose with the increase in sample size, effect size, and correlation coefficient for the matched pairs. In addition, lower type I errors were observed estimated by using the hybrid statistic, which indicates that this test is also conservative for data with outliers in the interim analysis of clinical trials.^

Improving disclosure of medical errors: Including patients and family members in the disclosure process

Over the last decade, adverse events and medical errors have become a main focus of interest for the standards of quality and safety in the U.S. healthcare system (Weinstein & Henderson, 2009). Particularly when a medical error occurs, the disclosure of medical errors and its practices have become a focal point of the healthcare process. Patients and family members who have experienced a medical error might be able to provide knowledge and insight on how to improve the disclose process. However, patient and family member are not typically involved in the disclosure process, thus their experiences go unnoticed. ^ The purpose of this research was to explore how best to include patients and family members in the disclosure process regarding a medical error. The research consisted of 28 qualitative interviews from three stakeholder groups: Hospital Administrators, Clinical Service Providers, and Patients and Family Members. They were asked for their ideas and suggestions on how best to include patients and family members in the disclosure process. Framework Analysis was used to analyze this data and find prevalent themes based on the primary research question. A secondary aim was to index categories created based on the interviews that were collected. Data was used from the Texas Disclosure and Compensation Study with Dr. Eric Thomas as the Principal Investigator. Full acknowledgement of access to this data is given to Dr. Thomas. ^ The themes from the research revealed that each stakeholder group was interested and open to including patients and family members in the disclosure process and that the disclosure process should not be a "one-way" avenue. The themes gave many suggestions regarding how to best include patients and family members in the disclosure process of a medical error. Secondary aims revealed several ways to assess the ideas and suggestion given by the stakeholders. Overall, acceptability of getting the perspective of patients and family members was the most common theme. Comparison of each stakeholder group revealed that including patients and family members would be beneficial to improving hospital disclosure practices. ^ Conclusions included a list of recommendations and measureable appropriate strategies that could provide hospital with key stakeholders insights on how to improve their disclosure process. Sharing patients and family members experience with healthcare providers can encourage a shift in culture where patients are valued and active in participating in hospital practices. To my knowledge, this research is the very first of its kind and moves the disclosure process conversation forward in a patient-family member inclusion direction that will assist in improving disclosure practices. Future research should implement and evaluate the success of the various inclusion strategies.^

Reconstructed pCO2 data from tree ring cellulose d13C during 1902-2005 at 10 sites in the Tropics and Northern Subtropics

This is the reconstructed pCO2 data from Tree ring cellulose d13C data with estimation errors for 10 sites (location given below) by a geochemical model as given in the publication by Trina Bose, Supriyo Chakraborty, Hemant Borgaonkar, Saikat Sengupta. This data was generated in Stable Isotope Laboratory, Indian Institute of Tropical Meteorology, Pune - 411008, India

Swath sonar bathymetry during SONNE cruise SO196 with links to multibeam raw data files

Multibeam data were measured during R/V Sonne cruise SO-196 (2008-03-02 to 2008-03-27) along survey profiles, transits and during stationary work. Data were achieved at the Okiwana Trough, particularly in the area of Yonaguni Knoll and Hatoma Knoll. The multibeam sonar system Kongsberg EM120 was operated using 191 beams and up to 150 deg aperture angle. The refraction correction was achieved using CTD profiles measured during this cruise. The quality of data might be reduced during bad weather periods. The dataset contains raw data that are not processed and thus may contain errors and blunders in depth and position.

Barents and Kara Seas oceanographic data base (BarKode)

Oceanographic data collected by ocean research organisations in Russia, the USA, the United Kingdom, Germany, Norway, and Poland for the Barents, Kara and White Seas region are presented in this atlas. Recently declassified naval data from Norway, the USA, and the UK are also included. More than 1,000,000 oceanographic stations containing temperature and/or sea-water salinity data were originally selected. After correcting errors and eliminating duplicates, data from 206,300 checked stations were placed on CD-ROM, together with many figures describing the characteristics of both the single-input and combined data set. In addition, temperature and salinity measurements were interpolated to the following standard horizons: 0, 25, 50, 100, 150, 200, 250, 300 m, and bottom. This atlas covers the 100-year period 1898 to 1998 and is, to date, the most complete oceanographic data collection for these Arctic shelf seas. This data set is complemented by more than 9,000 measurements of sea surface temperature, which were recently digitized from ships' logbooks. They cover the same geographical area within the time period 1867-1912.

Icebergs in the Amundsen Sea (Antarctica) determined from ENVISAT ASAR WSM data using object-based image analysis approach, link to ESRI GDB files

ENVISAT ASAR WSM images with pixel size 150 × 150 m, acquired in different meteorological, oceanographic and sea ice conditions were used to determined icebergs in the Amundsen Sea (Antarctica). An object-based method for automatic iceberg detection from SAR data has been developed and applied. The object identification is based on spectral and spatial parameters on 5 scale levels, and was verified with manual classification in four polygon areas, chosen to represent varying environmental conditions. The algorithm works comparatively well in freezing temperatures and strong wind conditions, prevailing in the Amundsen Sea during the year. The detection rate was 96% which corresponds to 94% of the area (counting icebergs larger than 0.03 km**2), for all seasons. The presented algorithm tends to generate errors in the form of false alarms, mainly caused by the presence of ice floes, rather than misses. This affects the reliability since false alarms were manually corrected post analysis.

Objective Mapping of Argo data in the Weddell Gyre: a gridded dataset of upper ocean water properties, link to data files in NetCDF format

The Weddell Gyre plays a crucial role in the regulation of climate by transferring heat into the deep ocean through deep and bottom water mass formation. However, our understanding of Weddell Gyre water mass properties is limited to regions of data availability, primarily along the Prime Meridian. The aim is to provide a dataset of the upper water column properties of the entire Weddell Gyre. Objective mapping was applied to Argo float data in order to produce spatially gridded, time composite maps of temperature and salinity for fixed pressure levels ranging from 50 to 2000 dbar, as well as temperature, salinity and pressure at the level of the sub-surface temperature maximum. While the data are currently too limited to incorporate time into the gridded structure, the data are extensive enough to produce maps of the entire region across three time composite periods (2002-2005, 2006-2009 and 2010-2013), which can be used to determine how representative conclusions drawn from data collected along general RV transect lines are on a gyre scale perspective. The time composite data sets are provided as netCDF files; one for each time period. Mapped fields of conservative temperature, absolute salinity and potential density are provided for 41 vertical pressure levels. The above variables as well as pressure are provided at the level of the sub-surface temperature maximum. Corresponding mapping errors are also included in the netCDF files. Further details are provided in the global attributes, such as the unit variables and structure of the corresponding data array (i.e. latitude x longitude x vertical pressure level). In addition, all files ending in "_potTpSal" provide mapped fields of potential temperature and practical salinity.

Swath sonar bathymetry during SONNE cruise SO202 (INOPEX) with links to multibeam raw data files

Multibeam data were measured during R/V SONNE cruise SO202 (INOPEX) along track lines of 6938 NM total length in the North Pacific and Bering Sea during transits and stationary work. Starting from Hokkaido (Japan) data were achieved east of the Kuril-Kamchatka Trench and south of the Aleutian Trench. The track crosses the Bowers Ridge, the continental margin of Alaska and the Umnak Plateau in the Bering Sea. Further data were gained in the North Pacific in the area of the Patton Seamounts, Gibson Seamount, Hess Rise and Shatsky Rise. The multibeam sonar system Simrad EM 120 from Kongsberg was operated using 191 beams and an aperture angle of 90° to 140° due to particular conditions. The refraction correction was achieved utilizing 6 CTD profiles measured during the cruise and one from cruise SO201. The quality of data might be reduced during bad weather periods. The dataset contains raw data that are not processed and thus may contain errors and blunders in depth and position.

Swath sonar bathymetry during POLARSTERN cruise ARK-XXII/1c (PS70) with links to multibeam raw data files

Multibeam data were measured as part of the project HERMES during R/V Polarstern cruise ARK-XXII/1 (2007-05-29 to 2007-07-25) along transits and survey profiles and partly during stationary work. Data were achieved mainly in the coastal areas of northern Norway, at the Hakon Mosby Mud Volcano at the continental margin approx. 200 nm off the norwegian coast and the AWI-Hausgarten area approx. 150 nm west of Svalbard. A number of surveys were carried out in the coastal areas of northern Norway (Sula Reef, Roest Reef, Traena area, Floholmen area, Sotbakken area) and around the area of the Hakon Mosby Mud Volcano. The multibeam sonar system Atlas Hydrosweep DS-2 (Atlas Hydrographic, http://www.atlashydro.com) was operated using 59 beams and 90° aperture angle. The refraction correction was achieved using CTD profiles measured during this cruise or, during transits, utilizing the system's own cross fan calibration. The quality of data might be reduced during bad weather periods or adverse sea ice conditions (only in the AWI-Hausgarten area). This dataset contains raw data that are not processed and thus may contain errors and blunders in depth and position.

Swath sonar bathymetry during POLARSTERN cruise ANT-XXVI/3 (PS75) with links to multibeam raw data files

Multibeam data were collected during R/V Polarstern cruise ANT-XXVI/3 along track lines of about 10,400 NM total length along transits, survey profiles and during stationary work. Departing in New Zealand the ship passed Pacific Antarctic Ridge heading to Ross Sea. Main working area was the Amundsen Sea and Bellingshausen Sea. Recorded bathymetry is supplementing existing tracks e.g. of R.V. James Clark Ross and R.V. Nathaniel B. Palmer. The refraction correction was achieved utilizing CTD profiles or by the system's own cross fan calibration. The quality of data might be reduced during bad weather periods or adverse sea ice conditions. The dataset contains raw data that are not processed and thus may contain errors and blunders in depth and position.

Swath sonar bathymetry during POLARSTERN cruise ANT-XVI/4 (PS53) with links to multibeam raw data files

Multibeam data were collected without operator supervision on R/V Polarstern cruise ANT-XVI/4 along track lines of 6385 NM total length. Data were achieved during transits and stationary work on the route from Cape Town to Bremerhaven via the Cape Verde Islands and the Canary Islands. The multibeam sonar system Hydrosweep DS-2 was operated using 59 beams and 90° aperture angle. The quality of data might be reduced during bad weather periods or adverse sea ice conditions. The dataset contains raw data that are not processed and thus may contain errors and blunders in depth and position.

Swath sonar bathymetry during POLARSTERN cruise ANT-XV/4 (PS49) with links to multibeam raw data files

Multibeam data were collected without operator supervision on R/V Polarstern cruise ANT-XV/4 along track lines of about 7000 NM total length. Data were achieved during transits and stationary work in the western Weddell Sea, at the Weddell-Scotia Confluence, and on a transect along the Prime Meridian of about 1300 NM length, between 69°S and 47°S. The multibeam sonar system Hydrosweep DS-2 was operated using 59 beams and 90° aperture angle. The quality of data might be reduced during bad weather periods or adverse sea ice conditions. The dataset contains raw data that are not processed and thus may contain errors and blunders in depth and position.