Analysis of Trends in Biospecimen Complexity in Cancer Research Over Two Decades.

Background: Over time, researchers' demand for increased quality and quantity of biospecimens has risen. However, quality is multifaceted, ranging from simple to complex, and comes at a cost. Therefore, to be sustainable and ensure optimal utilization of their resources (supply), biobanks must consider the trends in biospecimen use to predict the needs for future biospecimen quality (demand). Methods: An unbiased selection process was used to identify research articles from across the spectrum of cancer research from the PubMed database. A set of 225 articles utilizing human biospecimens were randomly selected for review (75 articles from each of three time intervals; 2000, 2010, 2020). Criteria for determining the source and complexity of quality of biospecimens were developed and overall concordance between two independent observers abstracting the data was then confirmed (k = 0.87) to validate the criteria. Results: We observed increased use of dual biospecimen formats (20%-36% of articles, p = 0.03), matched samples (16%-37% of articles, p = 0.0033), and biospecimens with associated outcomes data (20%-49%, p = 0.0002). In addition, the use of two or more cohorts increased over time (p = 0.03). The mechanism through which biospecimens were obtained also changed over time with an increase in the diversity of collection pathways used (p = 0.006). Conclusions: The complexity of biospecimens being used in cancer research and the diversity of collection pathways through which these are obtained has changed significantly. This observation is important for biobanks given that the cost to support the supply of biospecimens with complex extrinsic as opposed to simple intrinsic quality characteristics is greater. For biobanks to manage sustainability, optimize utilization, and meet changing research demand, they may need to adjust their operational models to better support the supply of these types of biospecimens.

Finding the Value in Biobanks: Enhancing the CTRNet Locator.

Biobanks are a critical piece of Research Infrastructure (RI). However, biobanks need to accept the reality of a life cycle for RIs. Until recently, strategies to sustain biobanks have been commonly focused on ways to maintain current operational models. However, sustaining biobanks as they exist today may be increasingly challenging in the face of the disruption in health and research priorities caused by the COVID-19 pandemic. In this opinion article, we review the current and emerging future drivers of biobank value for their researchers, institutions, and funders, highlighting utilization and impact of research performed using the biobank as key measures of future value. While biobanks can only indirectly influence the specific impact of the research performed, they can transform themselves to more actively redefine utilization to their advantage. Utilization means more than the balance of samples and data in versus out. Utilization means redirecting expertise to best support end users, and importantly, closing the operating gap between biobanks and their end users who seek to find the right biospecimens and data to pursue their research. We discuss the specific role of locators (those created by public investment) in closing this gap and the need for additional tools for researchers, before and subsequent to connecting with locators. For the former, we specifically propose that more support is needed to assist researchers in the decision as to how to best obtain biospecimens and navigate the options as to whether finding existing biospecimens and data held by a biobank is the optimal solution for a given project, or whether the optimal solution is either contracting with a biobank to collect samples or creating a new biobank. We believe this type of biospecimen navigator platform will help to maximize utilization of current biobank resources, and also promote the services and expertise in biobanks to better serve researchers' needs.

Vignettes to Illustrate the Value of Tumor Biobanks in Cancer Research in Canada.

Background: Tumor biobanks are a common research infrastructure. As a collection of biospecimens and annotated data collected to support a multitude of research projects, biobanks facilitate access to materials that are the critical fuel for the generation of data in up to 40% of cancer research publications. However, quantifying how to measure biobanks' impact and their value on the field of cancer research discoveries and findings, has not been well elucidated. Methods: We have used a qualitative case study approach to illustrate the impact of tumor biobanks. We assessed the impact of three research studies published between 2010 and 2012 that required easily accessible "classic" biobanks. Each study utilized preassembled collections of tumor biospecimens with associated patient outcomes data at the outset of the research project. We compared the resulting journal impact factor, altmetric and field-weighted citation impact factor scores for each article to a set of six "benchmark" articles that represent cancer research and treatment discoveries from the same time period and two sentinel scientific discovery articles. Results: We developed a value model using a literature search and design-thinking methodologies to illustrate the contributions of these "classic" model biobanks to these research studies. Assessment of the three example articles supported by biobanks demonstrates that the output can have impact that is comparable to the impact of a set of benchmark articles describing milestones in the field of cancer research and cancer care. Conclusions: These case studies illustrate the value of the sustained investment of funds, planning, time, and effort on the part of the biobanks before the conduct of the research study to be able to ultimately support high-value research. The "value" model will enable further discussion around impact and may be useful in better delineating qualitative metrics of biobank value in the future.

A Permission to Contact Platform Is an Efficient and Cost-Effective Enrollment Method for a Biobank to Create Study-Specific Research Cohorts.

Background: The permission to contact (PTC) platform is a useful mechanism to increase patient engagement and enrollment into biobanks. It provides biobanks with the ability to select specific patient cohorts and to complete consent to facilitate access to biospecimens and data. In this study, we evaluated consenting costs for a biobank to compile a research cohort based on utilizing a PTC platform to obtain consent as compared with utilizing a prospective consenting approach. Methods: In this study, we utilized a PTC platform to conduct an initial selection of potential participants for two breast cancer cohorts and to provide a "referral" to the biobank to recontact these patients to provide consent to access clinical archival biospecimens and associated data. We evaluated the effort, costs, and cohorts compiled by this approach to compare this mechanism with the alternative: compiling the same type of cohorts based on a classic biobank enrollment approach. Results: After initial diagnosis and provision of a PTC up to 12 years before, recontact was possible in 84 of 90 (74%) and 77 of 107 (72%) breast cancer patients for preinvasive (ductal carcinoma in situ [DCIS]) and invasive (triple-negative subtype) cancers. Of those recontacted, consent was completed in 42 of 84 (55%) DCIS patients and 48 of 107 (45%) triple negative breast cancer (TNBC) patients. The total cost of using PTC to recontact patients to compile these two consented cohorts was CAD $26.34 and CAD $20.11 per patient consent, respectively. Conclusions: We have demonstrated the feasibility of utilizing a PTC platform to obtain informed consent from patients for a specific study through referrals provided several years after initial PTC was provided. Depending on the existing biobank operational model and the efficiency of its processes for enrollment and obtaining broad informed consent, the implementation of a PTC platform may be an efficient and cost-effective complementary method for a biobank to enroll patients to develop criteria-specific cohorts to support research.

Comparison and Analysis of Two Internationally Recognized Biobanking Standards.

Impactful biobanking is underpinned by quality assurance and standardization. Several general biobank standards exist that can be associated with programs to provide different levels of conformity assessment, including the Canadian Tissue Repository Network (CTRNet) Certification program and the International Organization for Standardization (ISO) 20387 and accreditation bodies. We examined the CTRNet Required Operational Practices (2017) and ISO 20387 (2018), to compare them. Although the organization of each standard is different, both describe a set of discrete requirements (elements or subclauses) that comprise the standards that are contained in sections called chapters (CTRNet) or clauses (ISO). The standards have a similar number of requirements (CTRNet: 362, ISO: 322). To compare these standards, we reclassified the requirements in the ISO standard into 13 categories based on a combination of the chapter headings used in the ISBER and NCI Best Practices that represent important areas of biobanking activity. This categorization of requirements showed that each standard has a different emphasis reflected in different densities of requirements within distinct areas of biobanking. The ISO standard emphasizes Quality Management Systems whereas the CTRNet standard has an even coverage across the full spectrum of biobanking areas, including activities that are relevant to participant enrollment. Nevertheless, ∼60% of the requirements in the CTRNet standard match with those of the ISO standard. We conclude that these two standards have much in common but recommend that individual biobanks consider each standard carefully in the context of the purpose, focus, scale, and scope of their biobank to determine the appropriate standard to be followed.

Incidence of select chronic comorbidities among a population-based cohort of HIV-positive individuals receiving highly active antiretroviral therapy.

Objective: To characterize the incidence of select chronic comorbidities in the era of modern (pre-integrase-inhibitor) highly active antiretroviral therapy (HAART) in British Columbia, Canada. Methods: We used data from the Comparative Outcomes And Service Utilization Trends (COAST) study, a population-based cohort study of people living with HIV (PLWH), to determine incidence rates of six key chronic diseases among PLWH receiving HAART in BC from 2000 to 2012. The selected diseases included cardiovascular disease (CVD), diabetes mellitus (DM), hypertension (HTN), asthma/chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD) and chronic liver disease (CLD) defined using ICD-9 and -10 codes. Disease incidence was determined by number of new cases per year. We used Poisson regression to measure trends in incidence rates. Results: The study sample (n = 10,210) was predominantly male (83%), white (72%) and younger than 50 years of age at HAART initiation (88%). Incidence rates of HTN per 1000 person-years (PY) increased significantly between 2000 and 2012, after adjusting for age, sex, baseline-weighted Charlson Comorbidity Index, CD4 cell count and viral load (p < .001); incidence rates of CKD and CLD decreased significantly over time (p < .001). Unadjusted incidence rates of DM increased over time (p < .01), but remained stable in the adjusted model. Incidence rate patterns for CVD and COPD/asthma were stable over the study period. Conclusions: Population-level increases in incidence rates for HTN, and decreases for CLD and CKD, were observed among PLWH on modern (pre-integrase-inhibitor) HAART from 2000 to 2012. Overall, the increasing incidence of several of these chronic comorbidities in our study suggests that further efforts are needed to maximize the potential for healthy aging among PLWH receiving modern (pre-integrase-inhibitor) HAART.

Canadian Tissue Repository Network Biobank Certification Program: Update and Review of the Program from 2011 to 2018.

The Canadian Tissue Repository Network (CTRNet) Biobank Certification Program was first launched in 2011 to foster translational research through improved access to high quality biospecimens. This was accomplished by creating and providing biobank education and through the establishment and deployment of common standards to harmonize biospecimen quality and approaches to governance. The CTRNet program comprises registration and certification steps as two linked phases. In the two-step registration phase, the biobank is registered into the system, and an individual completes an overview educational module. In the subsequent certification phase, biobanks undergo a seven-step process, including inviting team members, assigning and completing relevant education modules, uploading documents, and undergoing a documentation audit. As of June 2018, there were 251 biobanks engaged in the CTRNet program, 193 had completed registration, and 40 were fully certified. Over 3/4 of these biobanks completed registration within a week and over 1/3 completed certification within a month. Among registered biobanks, 163 were associated with North American institutions, while 30 were from other international locations, including Australia, Europe, and Asia. The CTRNet program enables biobanks to adopt standards with a flexible approach to accommodate different types of biobanks and a measured investment of effort, creating the foundation for increased access to high quality biospecimens.

Predicting risk of mortality in dialysis patients: a retrospective cohort study evaluating the prognostic value of a simple chest X-ray.

BACKGROUND: Clinical outcomes of dialysis patients are variable, and improved knowledge of prognosis would inform decisions regarding patient management. We assessed the value of simple, chest X-ray derived measures of cardiac size (cardiothoracic ratio (CTR)) and vascular calcification (Aortic Arch Calcification (AAC)), in predicting death and improving multivariable prognostic models in a prevalent cohort of hemodialysis patients. METHODS: Eight hundred and twenty-four dialysis patients with one or more postero-anterior (PA) chest X-ray were included in the study. Using a validated calcification score, the AAC was graded from 0 to 3. Cox proportional hazards models were used to assess the association between AAC score, CTR, and mortality. AAC was treated as a categorical variable with 4 levels (0,1,2, or 3). Age, race, diabetes, and heart failure were adjusted for in the multivariable analysis. The criterion for statistical significance was p<0.05. RESULTS: The median CTR of the sample was 0.53 [IQR=0.48,0.58] with calcification scores as follows: 0 (54%), 1 (24%), 2 (17%), and 3 (5%). Of 824 patients, 152 (18%) died during follow-up. Age, sex, race, duration of dialysis, diabetes, heart failure, ischemic heart disease and baseline serum creatinine and phosphate were included in a base Cox model. Both CTR (HR 1.78[1.40,2.27] per 0.1 unit change), area under the curve (AUC)=0.60[0.55,0.65], and AAC (AAC 3 vs 0 HR 4.35[2.38,7.66], AAC 2 vs 0 HR 2.22[1.41,3.49], AAC 1 vs 0 HR 2.43[1.64,3.61]), AUC=0.63[0.58,0.68]) were associated with death in univariate Cox analysis. CTR remained significant after adjustment for base model variables (adjusted HR 1.46[1.11,1.92]), but did not increase the AUC of the base model (0.71[0.66,0.76] vs. 0.71[0.66,0.76]) and did not improve net reclassification performance (NRI=0). AAC also remained significant on multivariable analysis, but did not improve net reclassification (NRI=0). All ranges were based on 95% confidence intervals. CONCLUSIONS: Neither CTR nor AAC assessed on chest x-ray improved prediction of mortality in this prevalent cohort of dialysis patients. Our data do not support the clinical utility of X-ray measures of cardiac size and vascular calcification for the purpose of mortality prediction in prevalent hemodialysis patients. More advanced imaging techniques may be needed to improve prognostication in this population.

Serum creatinine measurement immediately after cardiac surgery and prediction of acute kidney injury.

BACKGROUND: After heart surgery, acute kidney injury (AKI) confers substantial long-term risk of death and chronic kidney disease. We hypothesized that small changes in serum creatinine (SCr) levels measured within a few hours of exit from the operating room could help discriminate those at low versus high risk of AKI. STUDY DESIGN: Prospective cohort of 350 elective cardiac surgery patients (valve or coronary artery bypass grafting) recruited in Winnipeg, Canada. Baseline SCr level was obtained at the preoperative visit 2 weeks before surgery. The postoperative SCr level was drawn within 6 hours of completion of surgery and then daily while the patient was in the hospital. PREDICTOR: Immediate (ie, <6 hours) postoperative SCr level change (ΔSCr), categorized as within 10% (reference), decrease >10%, or increase >10% relative to baseline. OUTCOME: AKI, defined according to the new KDIGO (Kidney Disease: Improving Global Outcomes) consensus definition as an increase in SCr level >0.3 mg/dL within 48 hours or >1.5 times baseline within 1 week. MEASUREMENTS: We compared the C statistic of logistic models with and without inclusion of immediate postoperative ΔSCr. RESULTS: After surgery, 176 patients (52%) experienced a decrease >10% in SCr level, 26 (7.4%) experienced an increase >10%, and 143 had ΔSCr within ±10% of baseline. During hospitalization, 53 (14%) developed AKI. Bypass pump time, baseline estimated glomerular filtration rate, and European System for Cardiac Operative Risk Evaluation (euroSCORE) were associated with AKI in a parsimonious base logistic model. Added to the base model, immediate postoperative ΔSCr was associated strongly with subsequent AKI and significantly improved model discrimination over the base model (C statistic, 0.78 [95% CI, 0.71-0.85] vs 0.69 [95% CI, 0.62-0.77]; P < 0.001). A ≥10% SCr level decrease predicted significantly lower AKI risk (OR, 0.37; 95% CI, 0.18-0.76), whereas a ≥10% SCr level increase predicted significantly higher (OR, 6.38; 95% CI, 2.37-17.2) AKI risk compared with the reference category. LIMITATIONS: We used a surrogate marker of AKI. External validation of our results is warranted. CONCLUSION: In elective cardiac surgery patients, measurement of immediate postoperative ΔSCr improves prediction of AKI.

Urinary hepcidin-25 and risk of acute kidney injury following cardiopulmonary bypass.

BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) complicating cardiopulmonary bypass (CPB) results in increased morbidity and mortality. Urinary hepcidin-25 has been shown to be elevated in patients who do not develop AKI after CPB using semiquantitative mass spectrometry (SELDI TOF-MS). The goals of this study were to quantitatively validate these findings with ELISA and evaluate the diagnostic performance of hepcidin-25 for AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A nested, case-control analysis of urinary hepcidin-25 in AKI (n = 22) and non-AKI (n = 22) patients was conducted to validate the SELDI TOF-MS data at the following times: preoperatively; the start of CPB; 1 hour on CPB; on arrival to the intensive care unit; and postoperative days (POD) 1 and 3 to 5. The diagnostic performance of hepcidin-25 was then evaluated in the entire prospective observational cohort (n = 338) at POD 1. AKI was defined as Cr >50% from baseline, within 72 hours postoperatively. RESULTS: Urinary hepcidin-25/Cr ratio was significantly elevated in all patients at POD 1 compared with baseline (P < 0.0005) and was also significantly elevated in non-AKI versus AKI patients at POD 1 (P < 0.0005). Increased log(10) hepcidin-25/Cr ratio was strongly associated with avoidance of AKI on univariate analysis. On multivariate analysis, the log(10) hepcidin-25/Cr ratio (P < 0.0001) was associated with avoidance of AKI with an area under the curve of 0.80, sensitivity 0.68, specificity 0.68, and negative predictive value 0.96. CONCLUSIONS: Elevated urinary hepcidin-25 on POD 1 is a strong predictor of avoidance of AKI beyond postoperative day 1.