Application of team science best practices to the project management of a large, multi-site lung cancer screening research consortium.

Research is increasingly conducted through multi-institutional consortia, and best practices for establishing multi-site research collaborations must be employed to ensure efficient, effective, and productive translational research teams. In this manuscript, we describe how the Population-based Research to Optimize the Screening Process Lung Research Center (PROSPR-Lung) utilized evidence-based Science of Team Science (SciTS) best practices to establish the consortium's infrastructure and processes to promote translational research in lung cancer screening. We provide specific, actionable examples of how we: (1) developed and reinforced a shared mission, vision, and goals; (2) maintained a transparent and representative leadership structure; (3) employed strong research support systems; (4) provided efficient and effective data management; (5) promoted interdisciplinary conversations; and (6) built a culture of trust. We offer guidance for managing a multi-site research center and data repository that may be applied to a variety of settings. Finally, we detail specific project management tools and processes used to drive collaboration, efficiency, and scientific productivity.

Developing an algorithm across integrated healthcare systems to identify a history of cancer using electronic medical records.

OBJECTIVE: Tumor registries in integrated healthcare systems (IHCS) have high precision for identifying incident cancer but often miss recently diagnosed cancers or those diagnosed outside of the IHCS. We developed an algorithm using the electronic medical record (EMR) to identify people with a history of cancer not captured in the tumor registry to identify adults, aged 40-65 years, with no history of cancer. MATERIALS AND METHODS: The algorithm was developed at Kaiser Permanente Colorado, and then applied to 7 other IHCS. We included tumor registry data, diagnosis and procedure codes, chemotherapy files, oncology encounters, and revenue data to develop the algorithm. Each IHCS adapted the algorithm to their EMR data and calculated sensitivity and specificity to evaluate the algorithm's performance after iterative chart review. RESULTS: We included data from over 1.26 million eligible people across 8 IHCS; 55 601 (4.4%) were in a tumor registry, and 44848 (3.5%) had a reported cancer not captured in a registry. The common attributes of the final algorithm at each site were diagnosis and procedure codes. The sensitivity of the algorithm at each IHCS was 90.65%-100%, and the specificity was 87.91%-100%. DISCUSSION: Relying only on tumor registry data would miss nearly half of the identified cancers. Our algorithm was robust and required only minor modifications to adapt to other EMR systems. CONCLUSION: This algorithm can identify cancer cases regardless of when the diagnosis occurred and may be useful for a variety of research applications or quality improvement projects around cancer care.

The association of bowel function, participation in life activities, and quality of life in rectal cancer survivors.

PURPOSE: To evaluate whether limited participation in life activities is associated with quality of life (QOL) in rectal cancer survivors, and if so, whether this association is independent of bowel function difficulties. METHODS: We surveyed rectal cancer survivors from four healthcare systems about their QOL, bowel function, and participation in life activities. Additional demographic and clinical variables were extracted from the electronic health record. We examined independent associations between bowel function, participation in life activities, and QOL, controlling for potential confounders. We also identified factors, including ostomy status, that correlate with participation in life activities. RESULTS: Of the 527 respondents, 52% were male, 80% were non-Hispanic white, and the mean age was 63. In fully adjusted models for all rectal cancer survivors, participation in life activities was positively associated with QOL, while bowel function was not. Bowel function retained an independent association with QOL for those who previously had an ostomy and were therefore more likely to have a low rectal anastomosis. Lower participation in life activities was correlated with lower self-reported physical and cognitive function, younger age, financial difficulty, and being non-Hispanic white. CONCLUSIONS: Rectal cancer survivors' participation in life activities was strongly associated with QOL, even when controlling for numerous confounders, including bowel function. Identifying ways to improve participation in life activities may be critical to developing rehabilitative and other supportive interventions that optimize QOL among rectal cancer survivors.

Characterizing employment of colorectal cancer survivors using electronic health records.

OBJECTIVE: Although the value of collecting occupational data is well-established, these data are not systematically collected in clinical practice. We assessed the availability of electronic health record (EHR)-based occupation data within a large integrated health care system to determine the feasibility of its use in research. MATERIALS AND METHODS: We used a mixed-methods approach to extract EHR data and define employment status, employer, and employment industry of 1107 colorectal cancer survivors. This was a secondary analysis of a subset of the Patient Outcomes Research to Advance Learning (PORTAL) colorectal cancer cohort. RESULTS: We categorized the employment industry for 46% of the cohort. Employment status was available for 58% of the cohort. The employer was missing for over 95% of the cohort. CONCLUSION: By combining data from structured and free-text EHR fields, we identified employment status and industry for approximately half of our sample. Findings demonstrate limitations of EHR data and underscore the need for systematic collection of occupation data in clinical practice.

Variation in Colorectal Cancer Stage and Mortality across Large Community-Based Populations: PORTAL Colorectal Cancer Cohort.

INTRODUCTION: Colorectal cancer (CRC) incidence and mortality can be reduced by effective screening and/or treatment. However, the influence of health care systems on disparities among insured patients is largely unexplored. METHODS: To evaluate insured patients with CRC diagnosed between 2010 and 2014 across 6 diverse US health care systems in the Patient-Centered Outcomes Research Institute (PCORI) Patient Outcomes Research To Advance Learning (PORTAL) CRC cohort, we contrasted CRC stage; CRC mortality; all-cause mortality; and influences of demographics, stage, comorbidities, and treatment between health systems. RESULTS: Among 16,211 patients with CRC, there were significant differences between health care systems in CRC stage at diagnosis, CRC-specific mortality, and all-cause mortality. The unadjusted risk of CRC mortality varied from 27% lower to 21% higher than the reference system (hazard ratio [HR] = 0.73, 95% confidence interval = 0.66-0.80 to HR = 1.21, 95% confidence interval = 1.05-1.40; p < 0.01 across systems). Significant differences persisted after adjustment for demographics and comorbidities (p < 0.01); however, adjustment for stage eliminated significant differences (p = 0.24). All-cause mortality among patients with CRC differed approximately 30% between health care systems (HR = 0.89-1.17; p < 0.01). Adjustment for age eliminated significant differences (p = 0.48). DISCUSSION: Differences in CRC survival between health care systems were largely explained by stage at diagnosis, not demographics, comorbidity, or treatment. Given that stage is strongly related to early detection, these results suggest that variation in CRC screening systems represents a modifiable systems-level factor for reducing disparities in CRC survival.

Changes in use of opioid therapy after colon cancer diagnosis: a population-based study.

PURPOSE: To describe patterns of opioid use in cancer survivors. METHODS: In a cohort study of colon cancer patients diagnosed during 1995-2014 and enrolled at two Kaiser Permanente regions, we constructed quarterly measures of opioid use from 1 year before cancer diagnosis through 5 years after diagnosis to examine changes in use. Measures included any use, incident use, regular use (use ≥ 45 days in a 91-day quarter), and average daily dose (converted to morphine milligram equivalent, MME). We also assessed temporal trends of opioid use. RESULTS: Of 2,039 colon cancer patients, 11-15% received opioids in the four pre-diagnosis quarters, 68% in the first quarter after diagnosis, and 15-17% in each subsequent 19 quarters. Regular opioid use increased from 3 to 5% pre-diagnosis to 5-7% post diagnosis. Average dose increased from 15 to 17 MME/day pre-diagnosis to 14-22 MME/day post diagnosis (excluding the quarter in which cancer was diagnosed). Among post-diagnosis opioid users, 73-95% were on a low dose (< 20 MME/day). Over years, regular use of opioids increased in survivorship with no change in dosage. CONCLUSION: Opioid use slightly increased following a colon cancer diagnosis, but high-dose use was rare. Research is needed to differentiate under- versus over-treatment of cancer pain.

Treatment patterns and survival differ between early-onset and late-onset colorectal cancer patients: the patient outcomes to advance learning network.

PURPOSE: Our objective was to describe differences in treatment patterns and survival between early-onset (< 50 years old) and late-onset colorectal cancer (CRC) patients in community-based health systems. METHODS: We used tumor registry and electronic health record data to identify and characterize patients diagnosed with adenocarcinoma of the colon or rectum from 2010 to 2014 at six US health systems in the patient outcomes to advance learning (PORTAL) network. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing the distribution of tumor characteristics and treatment patterns in early-onset versus late-onset CRC. Cox regression models were used to estimate adjusted hazard ratios (HRs) and CIs comparing survival between early- and late-onset CRC patients. RESULTS: There were 1,424 early-onset and 10,810 late-onset CRC cases in our analyses. Compared to late-onset CRC, early-onset CRC was significantly associated with advanced-stage disease, high-grade histology, signet ring histology, and rectal or left colon location. After adjusting for differences in tumor and patient characteristics, early-onset patients were more likely than late-onset patients to have > 12 lymph nodes examined (OR 1.60, CI 1.37-1.87), to receive systemic therapy (chemotherapy or immunotherapy) within 6 months of diagnosis (OR 2.84, CI 2.40-3.37), and to have a reduced risk of CRC-specific death (HR 0.66, CI 0.56-0.79). CONCLUSIONS: Early-onset CRC is associated with aggressive tumor characteristics, distal location, and systemic therapy use. Despite some adverse risk factors, these patients tend to have better survival than older onset patients.

Cardiovascular medication use and risks of colon cancer recurrences and additional cancer events: a cohort study.

BACKGROUND: Cardiovascular medications may be associated with cancer development, but little is known about their association with cancer recurrence. Medications such as statins and antihypertensives may be commonly used among colon cancer survivors, who are, on average, diagnosed in their mid-60s. We described the associations between statins and antihypertensive medications and colon cancer recurrence in a large, population-based study. METHODS: We conducted a cohort study among adults with stage I-IIIA colon cancer diagnosed in 1995-2014 in two Kaiser Permanente regions, Colorado and Washington. Statin and antihypertensive use were obtained from electronic pharmacy dispensing data. People were classified as medication users on the date of their first dispensing after cohort entry, which started 90 days after completing cancer treatment, continuing through the earliest of death, health plan disenrollment, or chart abstraction. We collected outcome information from medical record abstraction and tumor registries on colon cancer recurrences and second primary cancers. Using Cox proportional hazards multivariable models, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for colon cancer recurrences and any cancer event (recurrences and new primaries at any anatomic site) comparing medication users to non-users. RESULTS: Among 2039 people, 937 (46%) used statins and 1425 (70%) used antihypertensives at any point during a median of 4.9 years of follow-up; 460 people had any additional cancer event, including 152 with a colon cancer recurrence. Statin use was not associated with colon cancer recurrence (HR = 1.09, 95%CI = 0.65-1.85) or any cancer event (HR = 1.12, 95%CI = 0.85-1.47), nor was antihypertensive use associated with recurrence (HR = 0.73, 95%CI = 0.44-1.21) or any cancer event (HR = 0.93, 95%CI = 0.70-1.24). CONCLUSIONS: Our results suggest no association between cardiovascular medication use and the risk of recurrence or any additional cancer, and may provide reassurance to colon cancer survivors.

Use of antidepressants after colon cancer diagnosis and risk of recurrence.

OBJECTIVE: Prior research examining the association between use of antidepressants after colon cancer diagnosis and risk of recurrence is scant. We evaluated this association among colon cancer patients diagnosed at two integrated health care delivery systems in the United States. METHODS: We conducted a cohort study of stage I to IIIA colon cancer patients diagnosed at greater than or equal to 18 years of age at Kaiser Permanente Colorado and Kaiser Permanente Washington during 1995 to 2014. We used pharmacy records to identify dispensings for antidepressants and tumor registry records and patients' medical charts to identify cancer recurrences. Using Cox proportional hazards models, we estimated the adjusted hazard ratio (HR) of colon cancer recurrence comparing patients who used antidepressants after diagnosis to those who did not. We also evaluated the risk associated with use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) separately. RESULTS: Among the 1923 eligible colon cancer patients, 807 (42%) used an antidepressant after diagnosis and 139 had a colon cancer recurrence during an average 5.6 years of follow-up. Use of antidepressants after colon cancer diagnosis was not associated with risk of recurrence (HR: 1.14; 95% confidence interval [CI], 0.69-1.87). The HR for use of SSRIs was 1.22 (95% CI, 0.64-2.30), and for TCAs, it was 1.18 (95% CI, 0.68-2.07). CONCLUSIONS: Our findings suggest that use of antidepressants after colon cancer diagnosis was common and not associated with risk of recurrence. Future larger studies with greater power to examine risk associated with individual antidepressants would be valuable additions to the evidence base.

Risk of colon cancer recurrence in relation to diabetes.

PURPOSE: To describe the association between diabetes and colon cancer recurrence. METHODS: We conducted a cohort study at two integrated health care delivery systems in the United States. Using tumor registry data, we identified patients aged ≥ 18 years when diagnosed with stage I-IIIA adenocarcinomas of the colon during 1995-2014. Pre-existing diabetes was ascertained via diagnosis codes. Medical records were reviewed for eligibility and to abstract recurrence and covariate information. Recurrence was ascertained beginning 90 days after the end of colon cancer treatment (i.e., cohort entry). Recurrence of any cancer or a new primary cancer at any site was a secondary outcome. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for the associations between diabetes at cohort entry and study outcomes. RESULTS: Among the 1,923 eligible patients, 393 (16.7%) had diabetes at cohort entry. Diabetes was not associated with recurrence (HR 0.87; 95% CI 0.56-1.33) or with any subsequent cancer (HR 1.09; 95% CI 0.85-1.40). When the definition of recurrence included second primary colorectal cancer, risk was non-significantly higher in patients with diabetes than without diabetes. CONCLUSIONS: The risk of colon cancer recurrence appears to be similar in patients with and without diabetes at diagnosis. IMPACT: Future studies should evaluate the association between diabetes and colorectal cancer outcomes, especially second primary colon cancers, in larger populations.

Optimizing patient-reported outcome and risk factor reporting from cancer survivors: a randomized trial of four different survey methods among colorectal cancer survivors.

PURPOSE: The goal of this study was to determine response rates and associated costs of different survey methods among colorectal cancer (CRC) survivors. METHODS: We assembled a cohort of 16,212 individuals diagnosed with CRC (2010-2014) from six health plans, and randomly selected 4000 survivors to test survey response rates across four mixed-mode survey administration protocols (in English and Spanish): arm 1, mailed survey with phone follow-up; arm 2, interactive voice response (IVR) followed by mail; arm 3; email linked to web-based survey with mail follow-up; and arm 4, email linked to web-based survey followed by IVR. RESULTS: Our overall response rate was 50.2%. Arm 1 had the highest response rate (59.9%), followed by arm 3 (51.9%), arm 2 (51.2%), and arm 4 (37.9%). Response rates were higher among non-Hispanic whites in all arms than other racial/ethnic groups (p < 0.001), among English (51.5%) than Spanish speakers (36.4%) (p < 0.001), and among higher (53.7%) than lower (41.4%) socioeconomic status (p < 0.001). Survey arms were roughly comparable in cost, with a difference of only 8% of total costs between the most (arm 2) and least (arm 3) expensive arms. CONCLUSIONS: Mailed surveys followed by phone calls achieved the highest response rate; email invitations and online surveys cost less per response. Electronic methods, even among those with email availability, may miss important populations including Hispanics, non-English speakers, and those of lower socioeconomic status. IMPLICATIONS FOR CANCER SURVIVORS: Our results demonstrate effective methods for capturing patient-reported outcomes, inform the relative benefits/disadvantages of the different methods, and identify future research directions.

Improving quality of breast cancer surgery through development of a national breast cancer surgical outcomes (BRCASO) research database.

BACKGROUND: Common measures of surgical quality are 30-day morbidity and mortality, which poorly describe breast cancer surgical quality with extremely low morbidity and mortality rates. Several national quality programs have collected additional surgical quality measures; however, program participation is voluntary and results may not be generalizable to all surgeons. We developed the Breast Cancer Surgical Outcomes (BRCASO) database to capture meaningful breast cancer surgical quality measures among a non-voluntary sample, and study variation in these measures across providers, facilities, and health plans. This paper describes our study protocol, data collection methods, and summarizes the strengths and limitations of these data. METHODS: We included 4524 women ≥18 years diagnosed with breast cancer between 2003-2008. All women with initial breast cancer surgery performed by a surgeon employed at the University of Vermont or three Cancer Research Network (CRN) health plans were eligible for inclusion. From the CRN institutions, we collected electronic administrative data including tumor registry information, Current Procedure Terminology codes for breast cancer surgeries, surgeons, surgical facilities, and patient demographics. We supplemented electronic data with medical record abstraction to collect additional pathology and surgery detail. All data were manually abstracted at the University of Vermont. RESULTS: The CRN institutions pre-filled 30% (22 out of 72) of elements using electronic data. The remaining elements, including detailed pathology margin status and breast and lymph node surgeries, required chart abstraction. The mean age was 61 years (range 20-98 years); 70% of women were diagnosed with invasive ductal carcinoma, 20% with ductal carcinoma in situ, and 10% with invasive lobular carcinoma. CONCLUSIONS: The BRCASO database is one of the largest, multi-site research resources of meaningful breast cancer surgical quality data in the United States. Assembling data from electronic administrative databases and manual chart review balanced efficiency with high-quality, unbiased data collection. Using the BRCASO database, we will evaluate surgical quality measures including mastectomy rates, positive margin rates, and partial mastectomy re-excision rates among a diverse, non-voluntary population of patients, providers, and facilities.

Clinical outcomes using aggressive approach to anatomic screening and endovascular revascularization in a veterans affairs population with critical limb ischemia.

BACKGROUND: This study sought to examine the impact of an aggressive approach to anatomic screening and endovascular revascularization in a veterans administration population with critical limb ischemia (CLI) on the primary treatments received and overall clinical outcomes. METHODS: The baseline clinical and angiographic characteristics and clinical outcomes of the first consecutive fifty veterans who were referred for the evaluation and treatment of CLI using the strategy outlined were assessed by retrospective review of the computerized medical record and angiographic data. RESULTS: Among the entire cohort, the primary treatments received were as follows--revascularization n = 44 (88%), primary amputation n = 1 (2%), medical treatment n = 3 (6%), and primary minor amputation n = 2 (4%). Endovascular revascularization was the dominant mode of revascularization (94%), with a procedural success rate of 91%. Repeat revascularization was required in 19% of patients who had an initially successful endovascular procedure. A total of eight deaths and four major amputations occurred in the entire cohort over a mean follow-up of 397 +/- 190 days. The 1-year Kaplan-Meier estimates for survival and amputation-free survival for the entire cohort were 90 and 81%, respectively. Resolution of rest pain or complete wound healing was achieved in 85% of patients at a mean of 157 +/-126 days. CONCLUSIONS: An aggressive approach to anatomic screening and contemporary endovascular treatment of CLI resulted in a higher rate of revascularization as the primary treatment for CLI than previously reported, and was associated with high rates of overall and amputation-free survival.

Inferring the location of tumor suppressor genes by modeling frequency of allelic loss.

Allelic loss is often part of a multistep process leading to tumorigenesis. Analysis of genomic markers highlights regions of elevated allelic loss, which in turn suggests a nearby tumor suppressor. Furthermore, pooling published analyses to combine evidence can increase the power to detect a tumor suppressor gene. If the pattern of loss for each tumor, or allelotype, is known, a stochastic model proposed by Newton et al. (1998, Statistics in Medicine 17, 1425-1445) can be used to analyze the correlated binary data. Many studies report only incomplete allelotypes, augmented with frequencies of allelic loss (FAL) at each marker, in which the number of informative tumors showing allelic loss is provided along with the number of informative tumors. We describe an extension of the allelotype model to handle FAL data, using a hidden Markov model or a normal approximation to compute the likelihood. The FAL model is illustrated using data from a study of colorectal cancer.

Single- and multiple-dose pharmacokinetics of caspofungin in healthy men.

Caspofungin, a glucan synthesis inhibitor, is being developed as a parenteral antifungal agent. The pharmacokinetics of caspofungin following 1-h intravenous infusions in healthy men was investigated in four phase I studies. In an alternating two-panel (six men each), rising-single-dose study, plasma drug concentrations increased proportionally with the dose following infusions of 5 to 100 mg. The beta-phase half-life was 9 to 10 h. The plasma drug clearance rate averaged 10 to 12 ml/min. Renal clearance of unchanged drug was a minor pathway of elimination (approximately 2% of the dose). Multiple-dose pharmacokinetics were investigated in a 2-week, serial-panel (5 or 6 men per panel) study of doses of 15, 35, and 70 mg administered daily; a 3-week, single-panel (10 men) study of a dose of 70 mg administered daily; and a parallel panel study (8 men) of a dose of 50 mg administered daily with or without a 70-mg loading dose on day 1. Moderate accumulation was observed with daily dosing. The degree of drug accumulation and the time to steady state were somewhat dose dependent. Accumulation averaged 24% at 15 mg daily and approximately 50% at 50 and 70 mg daily. Mean plasma drug concentrations were maintained above 1.0 microg/ml, a target selected to exceed the MIC at which 90% of the isolates of the most clinically relevant species of Candida were inhibited, throughout therapy with daily treatments of 70 or 50 mg plus the loading dose, while they fell below the target for the first 2 days of a daily treatment of 50 mg without the loading dose. Caspofungin infused intravenously as a single dose or as multiple doses was generally well tolerated. In conclusion, the pharmacokinetics of caspofungin supports the clinical evaluation of once-daily dosing regimens for efficacy against fungal infections.