Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program.

BACKGROUND: The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]). RESULTS: Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen's d < 0.259, p < 7.80 × 10-4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p < 0.05) confounding in the GWAS statistics. CONCLUSIONS: This study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies.

Outcomes of robotic-assisted liver surgery versus laparoscopic liver surgery for treatment of stage I hepatocellular carcinoma.

BACKGROUND: This article investigated whether robotic-assisted liver surgery versus laparoscopic liver surgical treatment of hepatocellular carcinoma (HCC) has similar or different short- and long-term clinical outcomes. METHODS: A total of 3049 patients from the National Cancer Database who received minimally invasive surgery (ie, robotic or laparoscopic surgery) for stage I HCC cancers between 2010 to 2015, of which 123 had robotic and 2926 had laparoscopic surgeries performed, were identified. Logistic regression was applied to evaluate short-term outcomes. Cox proportional hazards models were applied to estimate all-cause mortality at 1-year, 3-years, and 5-years after surgery, adjusting for potential confounders. Propensity score-matched analyses were conducted to compare long-term outcomes between robotic and laparoscopic surgeries. RESULTS: Robotic surgery was associated with improved overall survival, with 1-, 3-, and 5-year survival rates (SRs) of 0.92, 0.75, and 0.63 compared with laparoscopic surgery SRs of 0.86, 0.60, and 0.45, respectively (P value <.01). Multivariate analyses showed that robotic compared with laparoscopic surgery had significantly lower 5-year total mortality (hazard ratio [HR], 0.64 and 95% confidence interval [CI], 0.45%-0.93% for intent-to-treat; HR, 0.62 and 95% CI, 0.42%-0.91% for end-treatment analyses). Similar results were found in propensity score matched analyses; robotic surgery was associated with improved overall survival compared with laparoscopic surgery (HR, 0.64 and 95% CI, 0.43%-0.96% for intent-to-treat; HR, 0.59 and 95% CI, 0.39%-0.90% for end-treatment). CONCLUSIONS: Robotic surgery is not inferior to laparoscopic surgery in treating early-stage HCC and may be associated with improved long-term survival.

Association of Gulf War Illness with Characteristics in Deployed vs. Non-Deployed Gulf War Era Veterans in the Cooperative Studies Program 2006/Million Veteran Program 029 Cohort: A Cross-Sectional Analysis.

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990-1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA's Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990-1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018-2019 survey, 35,902 respondents met study inclusion criteria, 13,107 deployed to the GW theater. GWI phenotypes were derived from Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions: (a) KS Symptoms (KS Sym+), (b) KS GWI (met symptom criteria and without exclusionary health conditions) [KS GWI: Sym+/Dx-], (c) CDC GWI and (d) CDC GWI Severe. The prevalence of each phenotype was 67.1% KS Sym+, 21.5% KS Sym+/Dx-, 81.1% CDC GWI, and 18.6% CDC GWI severe. These findings affirm the persistent presence of GWI among GW veterans providing a foundation for further exploration of biological and environmental underpinnings of this condition.

Patterns of Anticoagulation Use in Patients With Cancer With Atrial Fibrillation and/or Atrial Flutter.

BACKGROUND: Atrial fibrillation (AF) is a common cardiovascular complication affecting patients with cancer, but management strategies are not well established. OBJECTIVES: The purpose of this retrospective cohort study was to evaluate cross-sectional patterns of anticoagulation (AC) use in patients with cancer with AF or atrial flutter (AFL) on the basis of their risk for stroke and bleeding. METHODS: Patients with cancer and electrocardiograms showing AF or AFL performed at Moffitt Cancer Center in either the inpatient or outpatient setting were included in this retrospective analysis. We described percentages of AC prescription by stroke and bleeding risk, as determined by individual CHA2DS2-VASc and HAS-BLED scores, respectively. Multivariable logistic regression evaluated clinical variables independently associated with anticoagulant prescription. RESULTS: The prevalence of electrocardiography-documented AF or AFL was 4.8% (n = 472). The mean CHA2DS2-VASc score was 2.8 ± 1.4. Among patients with CHA2DS2-VASc scores ≥2 and HAS-BLED scores <3, 44.3% did not receive AC, and of these, only 18.3% had platelet values <50,000/µl. In multivariable analysis, older age, hypertension, prior stroke, and history of venous thromboembolism were each directly associated with AC use, while current chemotherapy use, prior bleeding, renal disease, and thrombocytopenia were each inversely associated with AC use. CONCLUSIONS: Nearly one-half of patients with cancer, the majority with normal platelet counts, had an elevated risk for stroke but did not receive AC. In addition to known predictors, current chemotherapy use was independently associated with a lower odds of AC use. This study highlights the need to improve the application of AF treatment algorithms to cancer populations.

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich's ataxia, and other rare iron-related diseases.

Background: Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information's (NCBI) Hackathon-model to take full advantage of local expertise in building "Iron Hack", a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich's ataxia, pitched at general audiences. Methods: The hackathon was structured to begin each day with presentations by expert clinicians, genetic counselors, researchers focused on molecular and cellular biology, public health/global health, genetics/genomics, computational biology, bioinformatics, biomolecular science, bioengineering, and computer science, as well as guest speakers from the American Porphyria Foundation (APF) and Friedreich's Ataxia Research Alliance (FARA) to inform participants as to the human impact of these diseases. Results: As a result of this hackathon, we developed resources that are relevant not only to these specific disease-models, but also to other rare diseases and general bioinformatics problems. Within two and a half days, "Iron Hack" participants successfully built collaborative projects to visualize data, build databases, improve rare disease diagnosis, and study rare-disease inheritance. Conclusions: The purpose of this manuscript is to demonstrate the utility of a hackathon model to generate prototypes of generalizable tools for a given disease and train clinicians and data scientists to interact more effectively.

Electronic medical record-verified hepatitis C virus screening in a large health system.

BACKGROUND: Baby boomers are at increased risk for hepatitis C virus (HCV) infection and related cancer; therefore, one-time HCV screening is recommended. METHODS: To assess prevalence of, and factors associated with providers ordering HCV screening, we examined a retrospective cohort of electronic medical records for patient visits from 01 August 2015 until 31 July 2017 in a large health system. HCV screening ordered was examined by patient age, gender, race/ethnicity, provider specialty, and number of clinical visits, stratified by birth cohort: born ≤1945, 1945-1965 (baby boomers), 1966-1985, and ≥1985. Multivariable regression identified factors independently associated with HCV screening ordered among average risk baby boomers. RESULTS: A total of 65 114 patients ages ≥18 years were evaluated. Among baby boomers HCV screening test order increased threefold between the two study years (4.0%-12.9%). Odds of screening test ordered were significantly higher for non-Hispanic Blacks (multivariable adjusted odds ratio [aOR]=1.36; 95% CI = 1.19-1.55), males (aOR = 1.44; 95% CI = 1.33-1.57), and having a clinic visit with a primary care provider alone or with specialty care (aOR = 3.25-4.16). Medicare (aOR = 0.89; 95% CI = 0.80-0.99), Medicaid (aOR 0.89; 95% CI 0.80-0.99), and an unknown provider type (aOR = 0.16; 95% CI = 0.08-0.33), were associated with lower odds of screening tests ordered. CONCLUSIONS: While the proportion of baby boomers with an HCV screening test ordered increased during the study, the rate of screening remains far below national goals. Data from this study indicate that providers are not ordering HCV screening universally for all of their baby boomer patients. Continued efforts to increase HCV screening are needed to reduce the incidence of HCV-related morbidity and mortality.

Hepatitis C virus screening trends: A 2016 update of the National Health Interview Survey.

BACKGROUND: 50% of liver cancer is caused by hepatitis C virus (HCV). Baby boomers are at increased risk and are recommended for one-time HCV screening. However, <13% of baby boomers were screened in 2015. MATERIALS AND METHODS: We are updating a previous study using 2013-2015 NHIS data to examine HCV screening prevalence by birth cohort, with 2016 data. We used logistic regression to evaluate whether HCV screening prevalence changed over time, stratified by birth cohort. RESULTS AND DISCUSSION: The sample consisted of 132,742 participants from 2013-2016. Screening increased in baby boomers from 11.9 to 14.1%. Odds of HCV screening for baby boomers was significantly associated with age, gender, race/ethnicity, and other variables and increased significantly with each subsequent year (aOR = 1.21, aOR = 1.33, aOR = 1.42, consecutively). While HCV screening is increasing over time, there is still room for improvement and future interventions should focus on increasing HCV screening among groups demonstrating significantly lower screening prevalence.

Descriptive epidemiology of malignant primary osteosarcoma using population-based registries, United States, 1999-2008.

BACKGROUND: Osteosarcoma is a rare bone tumor that is the most frequently diagnosed among children and adolescents, although this cancer affects people of all ages. This study aims to augment the current literature by examining the incidence of osteosarcoma by its subsites on a national level. METHODS: Data from central cancer registries in the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) programs for diagnosis years 1999-2008 and covering 90.1 percent of the US population were analyzed. Analyses included cases of malignant primary osteosarcomas, which were further segmented by topography, appendicular (C40) and axial (C41), to assess differences between these sites. Descriptive statistics, including estimated age-adjusted incidence rates standardized to the 2000 US standard population, were calculated using SEER*Stat 7.0.5 software. RESULTS: Approximately 7,104 cases of malignant primary osteosarcomas were identified during 1999-2008, of which 5,379 were appendicular and 1,725 were axial. The incidence of malignant primary osteosarcomas differed by age, gender, race, ethnicity, region, grade, and stage. These differences in incidence persisted when malignant primary osteosarcomas were categorized by topography codes. CONCLUSIONS: These analyses provide a better understanding of the incidence of malignant osteosarcoma which cover 90.1 percent of the US population from 1999-2008. This study provides a more detailed understanding of age, gender, race, and ethnicity by primary site for malignant osteosarcoma incidence on a national level in the United States. More importantly, differences between appendicular and axial sites were observed overall by selected demographic characteristics, in particular regional variations.

Using a state cancer registry to recruit young breast cancer survivors and high-risk relatives: protocol of a randomized trial testing the efficacy of a targeted versus a tailored intervention to increase breast cancer screening.

BACKGROUND: The Michigan Prevention Research Center, the University of Michigan Schools of Nursing, Public Health, and Medicine, and the Michigan Department of Community Health propose a multidisciplinary academic-clinical practice three-year project to increase breast cancer screening among young breast cancer survivors and their cancer-free female relatives at greatest risk for breast cancer. METHODS/DESIGN: The study has three specific aims: 1) Identify and survey 3,000 young breast cancer survivors (diagnosed at 20-45 years old) regarding their breast cancer screening utilization. 2) Identify and survey survivors' high-risk relatives regarding their breast cancer screening utilization. 3) Test two versions (Targeted vs. Enhanced Tailored) of an intervention to increase breast cancer screening among survivors and relatives. Following approval by human subjects review boards, 3,000 young breast cancer survivors will be identified through the Michigan Cancer Registry and mailed an invitation letter and a baseline survey. The baseline survey will obtain information on the survivors': a) current breast cancer screening status and use of genetic counseling; b) perceived barriers and facilitators to screening; c) family health history. Based on the family history information provided by survivors, we will identify up to two high-risk relatives per survivor. Young breast cancer survivors will be mailed consent forms and baseline surveys to distribute to their selected high-risk relatives. Relatives' baseline survey will obtain information on their: a) current breast cancer screening status and use of genetic counseling; and b) perceived barriers and facilitators to screening. Young breast cancer survivors and high-risk relatives will be randomized as a family unit to receive two versions of an intervention aiming to increase breast cancer screening and use of cancer genetic services. A follow-up survey will be mailed 9 months after the intervention to survivors and high-risk relatives to evaluate the efficacy of each intervention version on: a) use of breast cancer screening and genetic counseling; b) perceived barriers and facilitators to screening; c) self-efficacy in utilizing cancer genetic and screening services; d) family support related to screening; e) knowledge of breast cancer genetics; and f) satisfaction with the intervention. DISCUSSION: The study will enhance efforts of the state of Michigan surrounding cancer prevention, control, and public health genomics.

Descriptive epidemiology of malignant and nonmalignant primary spinal cord, spinal meninges, and cauda equina tumors, United States, 2004-2007.

BACKGROUND: Primary tumors of the spinal cord, spinal meninges, and cauda equina are relatively rare, and a paucity of population-based data exist on tumors in these sites. This study intends to augment the current literature by examining incidence of these tumors on a national level. METHODS: Data from central cancer registries in the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) programs for 2004-2007 (covering 99.2% of US population) and 1999-2007 (covering 89.4% of US population) were analyzed. Analyses for diagnosis years 2004-2007 included cases of malignant and nonmalignant primary spinal cord, spinal meninges, and cauda equina tumors. Descriptive statistics including estimated age-adjusted incidence rates standardized to the 2000 US standard population were conducted for both malignant and nonmalignant primary spinal tumors from cases diagnosed during 2004-2007 as well as trend analyses on malignant cases of primary spinal tumors (n = 5103) for cases diagnosed during 1999-2007 using SEER Stat 6.6.2 software. RESULTS: There were 2576 cases of malignant primary spinal tumors and 9136 cases of nonmalignant primary spinal tumors in 2004-2007. The incidence of malignant and nonmalignant primary spinal tumors combined differed by age, sex, race, and ethnicity. Results of trend analyses indicated that malignant primary spinal tumors have been stable throughout the 1999-2007 period. CONCLUSIONS: This large population-based study adds new insights into the descriptive epidemiology of primary spinal cord, spinal meninges, and cauda equina tumors by providing in-depth analyses of the incidence of these tumors on a national level.

A method to adjust for stage coding changes in the National Program of Cancer Registries illustrated for colorectal cancer.

We describe a simple statistical model that allows for a comparison of staging data from the Centers for Disease Control and Prevention's (CDC's) National Program of Cancer Registries during 1998-2008. In this program, cancers diagnosed during 1998-2000 were coded according to Summary Stage 1977, those diagnosed during 2001-2003 according to Summary Stage 2000, and those diagnosed during 2004-2008 according to the Collaborative Stage system. These changes in stage coding systems were associated with an abrupt shift in the distribution of extent of disease for colorectal cancer, particularly changes in the proportion of local vs regional stage disease, in some states. The method described here adjusts for the use of different staging systems over time so that temporal trends in the distribution of extent of disease can be evaluated. The method is applied to the proportion of localized stage colorectal cancer, but should be applicable to other cancers.

Evaluation of primary/preferred language data collection.

A literature review was conducted to identify peer-reviewed articles related to primary/preferred language and interpreter-use data collection practices in hospitals, clinics, and outpatient settings to assess its completeness and quality. In January 2011, Embase (Ovid), MEDLINE (Ovid), PubMed, and Web of Science databases were searched for eligible studies. Primary and secondary inclusion criteria were applied to selected eligible articles. This extensive literature search yielded 768 articles after duplicates were removed. After primary and secondary inclusion criteria were applied, 28 eligible articles remained for data abstraction. All 28 articles in this review reported collecting primary/preferred language data, but only 18% (5/28) collected information on interpreter use. This review revealed that there remains variability in the way that primary/preferred language and interpreter use data are collected; all studies used various methodologies for evaluating and abstracting these data. Likewise, the sources from which the data were abstracted differed.

Trends in endometrial cancer incidence rates in the United States, 1999-2006.

BACKGROUND: Risk factors for endometrial cancer, such as hormone replacement therapy (HRT) and obesity, have changed significantly in the last decade. We investigated trends in endometrial cancer histologic subtypes on a national level during 1999-2006. METHODS: Data covering 88% of the U.S. population were from central cancer registries in the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) programs that met high-quality United States Cancer Statistics (USCS) criteria. Our analyses included females with microscopically confirmed invasive uterine cancer (n=257,039). Age-adjusted incidence rates and trends for all invasive uterine cancers and by endometrial cancer histologic subtypes (type I and II) were assessed. RESULTS: There were 145,922 cases of type I endometrial cancers and 15,591 cases of type II for 1999-2006. We found that type I endometrial cancers have been increasing, whereas type II endometrial cancers and all invasive uterine cancers have been relatively stable throughout the 1999-2006 period. CONCLUSIONS: During the past decade, the overall burden of uterine cancer has been stable, although there have been changes in underlying histologies (e.g., endometrial). Changes in trends for underlying histologies may be masked when reviewing trends irrespective of histologic subtypes. Our findings suggest the need to examine trends of uterine cancer by histologic subtype in order to better understand the burden of endometrial cancer in relation to these subtypes to help women at increased risk for developing more aggressive types of endometrial cancer (e.g., type II).

Telomere length and variation in telomere biology genes in individuals with osteosarcoma.

Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents. Chromosomal aneuploidy is common in osteosarcoma cells, suggesting underlying chromosomal instability. Telomeres, located at chromosome ends, are essential for genomic stability; several studies have suggested that germline telomere length (TL) is associated with cancer risk. We hypothesized that TL and/or common genetic variation in telomere biology genes may be associated with risk of osteosarcoma. We investigated TL in peripheral blood DNA and 713 single nucleotide polymorphisms (SNPs) from 39 telomere biology genes in 98 osteosarcoma cases and 69 orthopedic controls. For the genotyping component, we added 1363 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer ScreeningTrial. Short TL was not associated with osteosarcoma risk overall (OR 1.39, P=0.67), although there was a statistically significant association in females (OR 4.35, 95% Cl 1.20-15.74, P=0.03). Genotype analyses identified seven SNPs in TERF1 significantly associated with osteosarcoma risk after Bonferroni correction by gene. These SNPs were highly linked and associated with a reduced risk of osteosarcoma (OR 0.48-0.53, P=0.0001-0.0006). We also investigated associations between TL and telomere gene SNPs in osteosarcoma cases and orthopedic controls. Several SNPs were associated with TL prior to Bonferroni correction; one SNP in NOLA2 and one in MEN1 were marginally non-significant after correction (P(adj)=0.057 and 0.066, respectively). This pilot-study suggests that females with short telomeres may be at increased risk of osteosarcoma, and that SNPs in TERF1 are inversely associated with osteosarcoma risk.

Comparative evaluation of uterine cancer staging data using two different staging systems, 2001-2005.

OBJECTIVE: This study compares directly coded Summary Stage 2000 (SS2000) with that of Collaborative Stage (CS) Derived Summary Stage 2000 (DeSS2000) for cases of uterine cancer diagnosed in the years 2001-2005 using population-based cancer registry data. METHODS: Data included in this study were from central cancer registries that participated in the Surveillance, Epidemiology, and End Results (SEER) Program or the National Program of Cancer Registries (NPCR) and met data quality criteria for 2001-2005 covering approximately 80% of the US population. The data for diagnosis years 2001-2003 (pre-CS) were compared with those for diagnosis years 2004-2005 (post-CS) to review any shifts in staging between the pre- and post-CS years. RESULTS: Slight decreases were observed in the percent of cases staged as in situ and localized uterine cancer with a corresponding slight increase in percent of regional and distant uterine cancer cases. In contrast to the findings in 2001-2003, no regional, (not otherwise specified) uterine cancer cases were reported in 2004-2005. Lastly, in the unstaged/unknown group of uterine cases, there was a slight decrease in the percent of cases. DISCUSSION: The lack of no regional, NOS, and the decrease in unstaged cases indicate improvement in staging of uterine cancer diagnosed in 2004-2005. These findings suggest that the CS DeSS2000 data are of high quality for uterine cancer and can be used to study the stage distribution of the cancer.