IDENTIFYING AND OVERCOMING BARRIERS IN THE TRANSLATION OF ETIOLOGIC CANCER BIOMARKERS

Background: With the goal to improve the translation of cancer biomarkers, this dissertation examined strategies to overcome two barriers in the practice of translational epidemiology: Aim 1) practice of multidisciplinary team science to overcome threats to validity, and Aim 2) use of quantitative metrics to determine the influence of continued investigation to improve utility of information from future biomarker investigations. Aim 1 and 2 strategies were used in Aim 3 to inform the analysis of multiple biomarkers of glycemia to better characterize the relationship between the natural history of diabetes and prostate cancer mortality. Methods: Aim 1 examined the impact of the practice of multidisciplinary team science on identifying and overcoming threats to validity. A case-study of a multidisciplinary team’s investigation of three tissue biomarkers where threats to validity were identified along with appropriate solutions through the practice of team science was carried out. In Aim 2 the impact of continued investigation of a biomarker-cancer relationship was quantified by adapting established research synthesis and clinical trial metrics – fail-safe number and conditional power analysis. To document how these metrics can be adapted to overcome the lack of utility of information from continued investigation, they were applied to a previously curated set of 98 meta-analyses of prospective studies investigating biomarkers and cancer risk. The strategies evaluated in Aims 1 and 2 were applied to Aim 3, by first identifying evidence gaps about the relationship between diabetes and prostate cancer followed by assembling a team with expertise in glycemia biomarkers and diabetes, and prostate cancer etiology. The team developed a refined strategy of incorporating multiple biomarkers of glycemia to better define normo- and hyperglycemia to investigate the relationship between the natural history of diabetes and prostate cancer in the Atherosclerosis Risk in Communities study. Results: Aim 1: Through the practice of team science, the multidisciplinary team consisting of a pathologist, cancer biologists, a biostatistician, and epidemiologist identified measurement error in the pre-analytic and analytic phase of the biomarker measurement, and was able to overcome the threats to validity by implementing appropriate corrections in the data analyses. Aim 2: Applying the fail-safe number and conditional power calculation to the 98 meta-analyses, we observed patterns in the characteristics of the existing evidence and the values of each of these metrics including the size of the observed summary estimate, the number of studies included in the observed meta-analysis, and the extent of between-study heterogeneity. Aim 3: After incorporating strategies from Aims 1 and 2, creating joint categories of the three glycemia biomarkers, and using men without diagnosed diabetes who had normal values for all three biomarkers as the reference group, men without diagnosed diabetes high on all three markers had close to a 5-fold increase in risk of prostate cancer death (HR: 4.80; 95% CI: 1.11 to 20.95). Men with diagnosed diabetes had a non-statistically significant 3-fold increase in risk of prostate cancer death. Conclusions: The inferential benefit achieved through the practice of multidisciplinary team science coupled with the adaptation of the fail-safe number and conditional power analysis to quantify the impact of continued biomarker investigation provide two strategies for the more efficient practice of translational epidemiology. Using these strategies to inform the analysis of biomarkers of glycemia and prostate cancer mortality, revealed an elevated risk of prostate cancer death in men without diagnosed diabetes with elevated glycemia and in men with diagnosed diabetes. These findings speak to the overall importance of diabetes prevention and good glycemic control in men with diagnosed diabetes

The Atacama Cosmology Telescope: Dynamical Masses and Scaling Relations for a Sample of Massive Sunyaev-Zel'dovich Effect Selected Galaxy Clusters

We present the first dynamical mass estimates and scaling relations for a sample of Sunyaev-Zel'dovich effect (SZE) selected galaxy clusters. The sample consists of 16 massive clusters detected with the Atacama Cosmology Telescope (ACT) over a 455 sq. deg. area of the southern sky. Deep multi-object spectroscopic observations were taken to secure intermediate-resolution (R~700-800) spectra and redshifts for ~60 member galaxies on average per cluster. The dynamical masses M_200c of the clusters have been calculated using simulation-based scaling relations between velocity dispersion and mass. The sample has a median redshift z=0.50 and a median mass M_200c~12e14 Msun/h70 with a lower limit M_200c~6e14 Msun/h70, consistent with the expectations for the ACT southern sky survey. These masses are compared to the ACT SZE properties of the sample, specifically, the match-filtered central SZE amplitude y, the central Compton parameter y0, and the integrated Compton signal Y_200c, which we use to derive SZE-Mass scaling relations. All SZE estimators correlate with dynamical mass with low intrinsic scatter (<~20%), in agreement with numerical simulations. We explore the effects of various systematic effects on these scaling relations, including the correlation between observables and the influence of dynamically disturbed clusters. Using the 3-dimensional information available, we divide the sample into relaxed and disturbed clusters and find that ~50% of the clusters are disturbed. There are hints that disturbed systems might bias the scaling relations but given the current sample sizes these differences are not significant; further studies including more clusters are required to assess the impact of these clusters on the scaling relations.Comment: 15 pages, 4 figures. Accepted for publication in The Astrophysical Journal; matches published version. Full Table 8 with complete spectroscopic member sample available in machine-readable form in the journal site and upon request to C. Sif\'o

Detection of intrinsic source structure at ~3 Schwarzschild radii with Millimeter-VLBI observations of SAGITTARIUS A*

We report results from very long baseline interferometric (VLBI) observations of the supermassive black hole in the Galactic center, Sgr A*, at 1.3 mm (230 GHz). The observations were performed in 2013 March using six VLBI stations in Hawaii, California, Arizona, and Chile. Compared to earlier observations, the addition of the APEX telescope in Chile almost doubles the longest baseline length in the array, provides additional {\it uv} coverage in the N-S direction, and leads to a spatial resolution of $\sim$30 $\mu$as ($\sim$3 Schwarzschild radii) for Sgr A*. The source is detected even at the longest baselines with visibility amplitudes of $\sim$4-13% of the total flux density. We argue that such flux densities cannot result from interstellar refractive scattering alone, but indicate the presence of compact intrinsic source structure on scales of $\sim$3 Schwarzschild radii. The measured nonzero closure phases rule out point-symmetric emission. We discuss our results in the context of simple geometric models that capture the basic characteristics and brightness distributions of disk- and jet-dominated models and show that both can reproduce the observed data. Common to these models are the brightness asymmetry, the orientation, and characteristic sizes, which are comparable to the expected size of the black hole shadow. Future 1.3 mm VLBI observations with an expanded array and better sensitivity will allow a more detailed imaging of the horizon-scale structure and bear the potential for a deep insight into the physical processes at the black hole boundary.Comment: 11 pages, 5 figures, accepted to Ap

The Atacama Cosmology Telescope: Sunyaev Zel'dovich Selected Galaxy Clusters at 148 GHz in the 2008 Survey

We report on twenty-three clusters detected blindly as Sunyaev-Zel'dovich (SZ) decrements in a 148 GHz, 455 square-degree map of the southern sky made with data from the Atacama Cosmology Telescope 2008 observing season. All SZ detections announced in this work have confirmed optical counterparts. Ten of the clusters are new discoveries. One newly discovered cluster, ACT-CL J0102-4915, with a redshift of 0.75 (photometric), has an SZ decrement comparable to the most massive systems at lower redshifts. Simulations of the cluster recovery method reproduce the sample purity measured by optical follow-up. In particular, for clusters detected with a signal-to-noise ratio greater than six, simulations are consistent with optical follow-up that demonstrated this subsample is 100% pure. The simulations further imply that the total sample is 80% complete for clusters with mass in excess of 6x10^14 solar masses referenced to the cluster volume characterized by five hundred times the critical density. The Compton y -- X-ray luminosity mass comparison for the eleven best detected clusters visually agrees with both self-similar and non-adiabatic, simulation-derived scaling laws.Comment: 13 pages, 7 figures, Accepted for publication in Ap