Choosing Wisely: Applying Value-Based Economic Principles to Population Science Research Investment.

Scientific research requires a substantial investment of time, effort, and money by researchers and funders. The funding that would be needed for all meritorious proposals far exceeds available resources. Major funding organizations use a multistep process for allocating research dollars that follows and extends beyond scientific peer review with considerations including mission priority, budget, and potential duplication of past or ongoing research activities. At the level of programmatic review, the process tends to be less proscribed than scientific review, but considerations relate to and are akin to basic value-driven economic principles. We propose a framework that encompasses the elements of programmatic review and provide examples of how the economic principles of opportunity costs, diminishing marginal productivity, sunk costs, economic optimization, return on investment, and option value apply to both research planning and funding decisions. Examples use cancer control population science research, as the nature of observational and interventional research involves large population studies (large sample size, recruitment, and often long-duration follow-up costs) which demand a high level of resource utilization; the same principles can be applied throughout medical and population health research. Awareness of the aspects of programmatic review and context to focus discussion regarding funding decisions may help guide research planning, decision-making, and increase transparency of the overall review process.

Use of Immunosuppression and the Risk of Subsequent Overall or Cancer Mortality.

PURPOSE: To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression. DESIGN: Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and CM for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression. PARTICIPANTS: Patients with noninfectious OID, excluding those with human immunodeficiency infection or preexisting cancer. METHODS: Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this noninterventional cohort study. MAIN OUTCOME MEASURES: Overall mortality and CM. RESULTS: Over 187 151 person-years (median follow-up 10.0 years), during which 15 938 patients were at risk for mortality, we observed 1970 deaths, 435 due to cancer. Both patients unexposed to immunosuppressants (standardized mortality ratio [SMR] = 0.95, 95% confidence interval [CI], 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SIDs) (SMR = 1.04, 95% CI, 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents with patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio [aHR] = 0.88, 0.89, 0.90, 1.11) and CM (aHR = 1.25, 0.89, 0.86, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3-, or 5-year lags and across quartiles of immunosuppressant dose and duration. CONCLUSIONS: Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and CM over a median cohort follow-up of 10.0 years. These results suggest the safety of these agents with respect to overall and CM for patients treated with immunosuppression for a wide range of inflammatory diseases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Awareness and use of genetic testing: An analysis of the Health Information National Trends Survey 2020.

PURPOSE: Genetic testing is a tool used in a variety of settings for medical and nonhealth related purposes. The goal of this analysis was to better understand the awareness and use of genetic testing in the United States. METHODS: Data from the 2020 Health Information National Trends Survey 5 cycle 4 were used to assess the awareness and use of genetic testing by demographic characteristics, personal cancer history, and family cancer history. RESULTS: Overall, 75% of participants were aware of genetic testing and 19% of participants had genetic testing. Ancestry testing was the most common type of testing that the participants were aware of and had received. Non-Hispanic Asian, Non-Hispanic Black, and Hispanic respondents and participants with incomes less than $20,000 were less likely to be aware of and have received any type of genetic testing than the Non-Hispanic White participants and participants with higher income, respectively. Participants with a family history of cancer were more likely to be aware of cancer genetic testing than those without, and participants with a personal history of cancer were more likely to have had cancer genetic testing. CONCLUSION: It appears awareness of genetic testing is increasing in the United States, and differences in awareness persist by race/ethnicity and income.

Applying the Strategic Planning Process to a Large Research Consortium: The Example of the National Cancer Institute Cohort Consortium.

Strategic planning is conducted by many organizations to systematically evaluate and assess their current state, establish or update their mission and/or goals, and identify strategies and activities to achieve the goals. The National Cancer Institute (NCI) Cohort Consortium is a collaborative network of 62 prospective cohort studies and their affiliated investigators that focus on cancer etiology and outcome research. The organization's membership grew markedly from 10 cohort studies at its inception in 2001 to 59 cohort studies at the time of the launch of the Consortium's strategic planning in 2017. This paper describes the strategic planning process that was conducted to establish organizational goals and to develop strategies and activities consistent with the Consortium's mission. The process involved a 2-year iterative approach combining surveys and in-person meetings. The resulting goals focus on communication, career development, research facilitation, scientific gaps, and common scientific challenges. The NCI Cohort Consortium's strategic plan and evaluation of its progress will advance new initiatives in cancer etiology and survivorship research.

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

BACKGROUND: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. METHODS: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. RESULTS: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. CONCLUSIONS: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. IMPACT: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

Utilizing SEER Cancer Registries for Population-Based Cancer Survivor Epidemiologic Studies: A Feasibility Study.

BACKGROUND: While the primary role of central cancer registries in the United States is to provide vital information needed for cancer surveillance and control, these registries can also be leveraged for population-based epidemiologic studies of cancer survivors. This study was undertaken to assess the feasibility of using the NCI's Surveillance, Epidemiology, and End Results (SEER) Program registries to rapidly identify, recruit, and enroll individuals for survivor research studies and to assess their willingness to engage in a variety of research activities. METHODS: In 2016 and 2017, six SEER registries recruited both recently diagnosed and longer-term survivors with early age-onset multiple myeloma or colorectal, breast, prostate, or ovarian cancer. Potential participants were asked to complete a survey, providing data on demographics, health, and their willingness to participate in various aspects of research studies. RESULTS: Response rates across the registries ranged from 24.9% to 46.9%, with sample sizes of 115 to 239 enrolled by each registry over a 12- to 18-month period. Among the 992 total respondents, 90% answered that they would be willing to fill out a survey for a future research study, 91% reported that they would donate a biospecimen of some type, and approximately 82% reported that they would consent to have their medical records accessed for research. CONCLUSIONS: This study demonstrated the feasibility of leveraging SEER registries to recruit a geographically and racially diverse group of cancer survivors. IMPACT: Central cancer registries are a source of high-quality data that can be utilized to conduct population-based cancer survivor studies.

A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.

BACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Expected Monetary Impact of Oncotype DX Score-Concordant Systemic Breast Cancer Therapy Based on the TAILORx Trial.

BACKGROUND: TAILORx demonstrated that women with node-negative, hormone receptor-positive, HER2-negative breast cancers and Oncotype DX recurrence scores (RS) of 0-25 had similar 9-year outcomes with endocrine vs chemo-endocrine therapy; evidence for women aged 50 years and younger and RS 16-25 was less clear. We estimated how expected changes in practice following the trial might affect US costs in the initial 12 months of care (initial costs). METHODS: Data from Surveillance, Epidemiology, and End Results (SEER), SEER-Medicare, and SEER-Genomic Health Inc datasets were used to estimate Oncotype DX testing and chemotherapy rates and mean initial costs pre- and post-TAILORx (in 2018 dollars), assuming all women received Oncotype DX testing and score-suggested therapy posttrial. Sensitivity analyses tested the impact on costs of assumptions about compliance with testing and score-suggested treatment and estimation methods. RESULTS: Pretrial mean initial costs were $2.816 billion. Posttrial, Oncotype DX testing costs were projected to increase from $115 to $231 million and chemotherapy use to decrease from 25% to 17%, resulting in initial care costs of $2.766 billion, or a net savings of $49 million (1.8% decrease). A small net savings was seen under most assumptions. The one exception was if all women aged 50 years and younger with tumors with RS 16-25 elected to receive chemotherapy, initial care costs could increase by $105 million (4% increase). CONCLUSIONS: Personalizing breast cancer treatment based on tumor genetic profiles could result in small cost decreases in the initial 12 months of care. Studies are needed to evaluate the long-term costs and nonmonetary benefits of personalized cancer care.

A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk.

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness (P heterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.

Anti-Müllerian hormone and risk of ovarian cancer in nine cohorts.

Animal and experimental data suggest that anti-Müllerian hormone (AMH) serves as a marker of ovarian reserve and inhibits the growth of ovarian tumors. However, few epidemiologic studies have examined the association between AMH and ovarian cancer risk. We conducted a nested case-control study of 302 ovarian cancer cases and 336 matched controls from nine cohorts. Prediagnostic blood samples of premenopausal women were assayed for AMH using a picoAMH enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted conditional logistic regression. AMH concentration was not associated with overall ovarian cancer risk. The multivariable-adjusted OR (95% CI), comparing the highest to the lowest quartile of AMH, was 0.99 (0.59-1.67) (Ptrend : 0.91). The association did not differ by age at blood draw or oral contraceptive use (all Pheterogeneity : ≥0.26). There also was no evidence for heterogeneity of risk for tumors defined by histologic developmental pathway, stage, and grade, and by age at diagnosis and time between blood draw and diagnosis (all Pheterogeneity : ≥0.39). In conclusion, this analysis of mostly late premenopausal women from nine cohorts does not support the hypothesized inverse association between prediagnostic circulating levels of AMH and risk of ovarian cancer.

"We're Just Not Prepared for Eating Over Our Whole Life": A Mixed Methods Approach to Understanding Dietary Behaviors Among Longer Term Cancer Survivors.

BACKGROUND: In many countries, there are growing numbers of persons living with a prior diagnosis of cancer, due to the aging population and more successful strategies for treatment. There is also growing evidence of the importance of healthful diet and weight management for survivorship, yet many long-term cancer survivors are not successfully following recommendations. METHODS: We explored this issue in a mixed methods study with 53 adult survivors of 3 cancers (breast, prostate, and non-Hodgkin's lymphoma), living in Maryland. Participants provided three 24-hour dietary recalls, and results were used to classify respondents on 2 metrics of healthful eating (the Healthy Eating Index 2010, and a 9-item index based on current dietary recommendations). Recalls were also used to guide in-depth qualitative discussions with participants regarding self-assessment of dietary behaviors, healthful eating, and diet's importance in cancer prevention and survivorship. RESULTS: Survivors following a more healthful diet were more likely to be female, have greater socioeconomic resources, more years since diagnosis, normal weight, and no smoking history. Qualitative discussions revealed a more nuanced understanding of dietary strategies among healthful eaters, as well as the importance of household members in dietary decision making. DISCUSSION: Most survivors had received little nutrition counseling as part of their cancer care, highlighting the importance of holistic, household-oriented nutrition education for maintaining health among long-term cancer survivors.

Updating the landscape of direct-to-consumer pharmacogenomic testing.

Pharmacogenomics has identified important drug-gene interactions that affect the safety and efficacy of medications. Direct-to-consumer genetic testing, when first introduced, included some pharmacogenomic-related genes. The current landscape of pharmacogenomic direct-to-consumer testing is reviewed. Prior published reviews of the literature were updated through February 2017 and a scan of the current availability of direct-to-consumer genomic testing by companies was conducted. Results of the review demonstrate a shift toward physician-approved ordering.

Anti-Mullerian hormone and endometrial cancer: a multi-cohort study.

BACKGROUND: The Mullerian ducts are the embryological precursors of the female reproductive tract, including the uterus; anti-Mullerian hormone (AMH) has a key role in the regulation of foetal sexual differentiation. Anti-Mullerian hormone inhibits endometrial tumour growth in experimental models by stimulating apoptosis and cell cycle arrest. To date, there are no prospective epidemiologic data on circulating AMH and endometrial cancer risk. METHODS: We investigated this association among women premenopausal at blood collection in a multicohort study including participants from eight studies located in the United States, Europe, and China. We identified 329 endometrial cancer cases and 339 matched controls. Anti-Mullerian hormone concentrations in blood were quantified using an enzyme-linked immunosorbent assay. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) across tertiles and for a doubling of AMH concentrations (ORlog2). Subgroup analyses were performed by ages at blood donation and diagnosis, oral contraceptive use, and tumour characteristics. RESULTS: Anti-Mullerian hormone was not associated with the risk of endometrial cancer overall (ORlog2: 1.07 (0.99-1.17)), or with any of the examined subgroups. CONCLUSIONS: Although experimental models implicate AMH in endometrial cancer growth inhibition, our findings do not support a role for circulating AMH in the aetiology of endometrial cancer.

Demographic, lifestyle, and other factors in relation to antimüllerian hormone levels in mostly late premenopausal women.

OBJECTIVE: To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimüllerian hormone (AMH) concentrations in mostly late premenopausal women. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 671 premenopausal women not known to have cancer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. RESULT(S): Older women had significantly lower AMH concentrations (≥40 [n = 444] vs. <35 years [n = 64], multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (<12 [n = 96] vs. ≥14 years [n = 200]: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). CONCLUSION(S): Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.

Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies.

BACKGROUND: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. METHODS: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. RESULTS: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, Pheterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, Ptrend < .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, Pheterogeneity = .08). CONCLUSIONS: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.

A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk.

The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288-300. ©2016 AACR.