Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

Patient desire for spiritual assessment is unmet in urban and rural primary care settings.

BACKGROUND: Incorporation of patient religious and spiritual beliefs in medical care has been shown to improve the efficacy of medical interventions and health outcomes. While previous study has highlighted differences in patient desire for spiritual assessment based on patient religiosity, little is known about patient desire for spiritual assessment based on community type, particularly in urban compared to rural communities. We hypothesized that, given demographic trends which show a higher degree of religiosity in rural areas, patients in rural communities will be more likely to desire spiritual assessment. METHODS: In this cross-sectional study of 141 adult primary care patients in rural and urban Colorado at non-religiously affiliated clinics, we surveyed patient demographic information, measures of religiosity, patient desire for spiritual assessment, and frequency of spiritual assessment in practice. Univariate logistic regression analyses were used to compare the two populations. RESULTS: In both Denver County (urban) and Lincoln County (rural) over 90% of patients identified as religious, spiritual, or a combination of the two. Thirty eight percent (38.3%) of patients in Denver County and 49.1% of patients in Lincoln desired spiritual assessment. Over 97% of patients in both areas reported rarely or never being asked about their R/S within the past year. For patients who have had five or more clinic visits in the past year, more than 91% in both areas stated they have never or rarely been asked about their beliefs. CONCLUSIONS: While the majority of patients in this study identify as religious or spiritual and many patients desire spiritual assessment, the majority of patients have never or rarely been asked about their spirituality within the past year. This demonstrates a significant gap between patient preference and provider practice of spiritual assessment in the primary care setting, which was similar in both rural and urban settings. This highlights the need for interdisciplinary focus on spiritual assessment and incorporation of patient R/S beliefs in medical care to provide holistic patient care and improve health outcomes.

Research participant understanding and engagement in an institutional, self-consent biobank model.

The number of institutional and governmental biobanks and the target enrollment sizes of modern biobanks are increasing, affording more opportunities for the public to participate in biobanking efforts. In parallel with these expansions are pressures to increase the efficiency of obtaining informed consent using shorter consent forms that cover a broader scope of research and increasingly include provisions for return of research or clinical genetic test results to participants. Given these changes, how well these participants understand genetics, their level of understanding of what they are consenting to, and their wishes to engage longitudinally and receive biobank results are not well understood. We surveyed participants in a large, medical system-based biobank who had enrolled through a two-page, self-consent process about their baseline knowledge of genetics, understanding and recall of the consent process, wishes for future contact and engagement, and level of interest in receiving clinical genetic testing results. A total of 856 consented persons participated in the survey (67% women; 67% white). Participants' general reported genetics knowledge was relatively high (mean 11.60 of 15 questions answered correctly) as was recall of key elements from the two-page consent form. Overall participant enthusiasm for future contact by the biobank and for receiving clinical genetic testing results was high. The use of a two-page, self-consent process in a large, institutional biobank resulted in high levels of consent recall and enthusiasm for future ongoing engagement and receipt of genetic testing results by participants.

Duties When an Anonymous Student Health Survey Finds a Hot Spot of Suicidality.

Public health agencies regularly survey randomly selected anonymous students to track drug use, sexual activities, and other risk behaviors. Students are unidentifiable, but a recent project that included school-level analysis discovered a school with alarmingly prevalent student suicidality. Given confidentiality protocols typical of surveillance, the surveyors were uncertain whether and how to intervene. We searched literature for duties to warn at-risk groups discovered during public health surveillance, but we found no directly applicable guidance or cases. Reasoning by analogy, we conclude that surveyors should contact the school's leaders to call attention to its outlier status, but public warning is unwarranted. However, such an ad hoc decision to issue a warning, even if only to school leaders, raises significant practical, legal and ethical issues. National public health and education associations should produce guidance that clarifies ethical and legal duties owed to schools and students involved in population health-risk surveillance.

A randomized trial of heart failure disease management in skilled nursing facilities (SNF Connect): Lessons learned.

BACKGROUND/AIMS: Conducting clinical trials in skilled nursing facilities is particularly challenging. This manuscript describes facility and patient recruitment challenges and solutions for clinical research in skilled nursing facilities. METHODS: Lessons learned from the SNF Connect Trial, a randomized trial of a heart failure disease management versus usual care for patients with heart failure receiving post-acute care in skilled nursing facilities, are discussed. Description of the trial design and barriers to facility and patient recruitment along with regulatory issues are presented. RESULTS: The recruitment of Denver-metro skilled nursing facilities was facilitated by key stakeholders of the skilled nursing facilities community. However, there were still a number of barriers to facility recruitment including leadership turnover, varying policies regarding research, fear of litigation and of an increased workload. Engagement of facilities was facilitated by their strong interest in reducing hospital readmissions, marketing potential to hospitals, and heart failure management education for their staff. Recruitment of patients proved difficult and there were few facilitators. Identified patient recruitment challenges included patients being unaware of their heart failure diagnosis, patients overwhelmed with their illness and care, and frequently there was no available proxy for cognitively impaired patients. Flexibility in changing the recruitment approach and targeting skilled nursing facilities with higher rates of admissions helped to overcome some barriers. CONCLUSION: Recruitment of skilled nursing facilities and patients in skilled nursing facilities for clinical trials is challenging. Strategies to attract both facilities and patients are warranted. These include aligning study goals with facility incentives and flexible recruitment protocols to work with patients in "transition crisis."

The ethics of using transgenic non-human primates to study what makes us human.

A flood of comparative genomic data is resulting in the identification of human lineage-specific (HLS) sequences. As apes are our closest evolutionary relatives, transgenic introduction of HLS sequences into these species has the greatest potential to produce 'humanized' phenotypes and also to illuminate the functions of these sequences. We argue that such transgenic apes would also be more likely than other species to experience harm from such research, which renders such studies ethically unacceptable in apes and justifies regulatory barriers between these species and other non-human primates for HLS transgenic research.

Ethical precepts for medical volunteerism: including local voices and values to guide RHD surgery in Rwanda.

At the invitation of the Rwandan Government, Team Heart, a team of American healthcare professionals, performs volunteer rheumatic heart disease (RHD) surgery in Rwanda every year, and confronts ethical concerns that call for cultural sensitivity. This article describes how five standard bioethical precepts are applied in practice in medical volunteerism related to RHD surgery in Rwanda. The content for the applied precepts stems from semiscripted, transcribed conversations with the authors, two Rwandan cardiologists, a Rwandan nurse and a Rwandan premedical student. The conversations revealed that the criteria for RHD surgical selection in Rwanda are analogous to the patient-selection process involving material scarcity in the USA. Rwandan notions of benefit and harm focus more attention on structural issues, such as shared benefit, national reputation and expansion of expertise, than traditional Western notions. Harm caused by inadequate patient follow-up remains a critical concern. Gender disparities regarding biological and social implications of surgical valve choices impact considerations of justice. Individual agency remains important, but not central to Rwandan concepts of justice, transparency and respect, particularly regarding women. The Rwandan understanding of standard bioethical precepts is substantively similar to the traditionally recognised interpretation with important contextual differences. The communal importance of improving the health of a small number of individuals may be underestimated in previous literature. Moreover, openness and the incorporation of Rwandan stakeholders in difficult ethical choices and long-term contributions to indigenous medical capacity appear to be valued by Rwandans. These descriptions of applied precepts are applicable to different medical missions in other emerging nations following a similar process of inclusion.

Large scale proteomic studies create novel privacy considerations.

Privacy protection is a core principle of genomic but not proteomic research. We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS), calculated continuous protein level genotype probabilities, and then applied a naïve Bayesian approach to link SomaScan 1.3K proteomes to genomes for 2812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA). We correctly linked 90-95% of proteomes to their correct genome and for 95-99% we identify the 1% most likely links. The linking accuracy in subjects with African ancestry was lower (~ 60%) unless training included diverse subjects. With larger profiling (SomaScan 5K) in the Atherosclerosis Risk Communities (ARIC) correct identification was > 99% even in mixed ancestry populations. We also linked proteomes-to-proteomes and used the proteome only to determine features such as sex, ancestry, and first-degree relatives. When serial proteomes are available, the linking algorithm can be used to identify and correct mislabeled samples. This work also demonstrates the importance of including diverse populations in omics research and that large proteomic datasets (> 1000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered unidentifiable.

Informed consent process in Alpha-1 testing of at-risk children: views of parents and adults tested as children.

Targeted testing programs are identifying increasing numbers of adults affected by Alpha-1 Antitrypsin Deficiency (Alpha-1) who are making decisions about genetic testing for their at-risk children. Although there are possible benefits, there are also potential risks. The purpose of this pilot study was to explore attitudes toward testing at-risk children from the first hand perspective of those involved, identify the benefits and risks experienced therein, and compare the views of parents and adults tested as children (ATC). The results of this pilot study suggest that ATC were significantly more favorable to including children in testing decisions than parents. ATC strongly indicated that they want to be involved in the testing decision and give permission prior to testing (p = 0.007). While the majority of ATC and parents were in favor of newborn screening for Alpha-1, parents had more extreme views, both positive and negative (p = 0.04). Both ATC and parents expressed significantly higher likelihoods of possible risks and benefits following Alpha-1 testing than they actually experienced. Results do not reveal serious harms from testing at-risk children. The two groups indicated that they want information regarding access to insurance, inheritance and expression, impact on anxiety, association with smoking, and usefulness in future planning prior to a decision to test or not to test at risk children. From the resulting data and ethical analysis we recommend that parents and children have relevant information prior to testing for Alpha-1 and that at risk children are directly involved in the decision-making process prior to testing.

Patient Perspectives on Religiously Affiliated Care in Rural and Urban Colorado.

INTRODUCTION: Religiously affiliated healthcare organizations play an important role in the delivery of care in the United States. There is a gap in the literature regarding patients' attitudes toward receiving care at these institutions, especially in geographically diverse populations. METHODS: In this two-site pilot study, we conducted a written survey of 141 adult primary care patients at non-religiously affiliated clinics in rural and urban Colorado. Demographic information, measures of religiosity and spirituality, and opinions regarding religiously affiliated care were collected. RESULTS: 73.3% and 69.6% of patients in rural and urban counties, respectively, had no preference as to the religious affiliation of their care. However, patients in the urban county (24.1%) were more likely than those in the rural county (8.3%) to prefer care that was not affiliated with any religion. CONCLUSIONS: This study suggests that concerns such as proximity to care and patient/provider relationships may be more important to patients than the possible religious affiliation of a healthcare organization. This work is a first step in better understanding patients' attitudes toward religiously affiliated care in urban versus rural settings.

A stakeholder engagement method navigator webtool for clinical and translational science.

Stakeholder engagement is increasingly expected by funders and valued by researchers in clinical and translational science, yet many researchers lack access to expert consultation or training in selecting appropriate stakeholder engagement methods. We describe the development of a novel Stakeholder Engagement Navigator webtool. We conducted an environmental scan and literature review, along with investigator interviews, surveys, and engagement expert facilitated group discussion. We formally reviewed and cataloged 29 distinct engagement methods. To develop the webtool, we used an iterative design process that followed Design Thinking phases: empathize, define, ideate, prototype, and test. As prioritized during user testing, the Stakeholder Engagement Navigator webtool both educates and guides investigators in selecting an engagement method based on key criteria. The V1.0 Navigator webtool filters methods first by purpose of engagement (noted by 62% of users as the highest priority criteria), then by budget, time per stakeholder interaction, and total interactions. The tool is available at DICEMethods.org. The Stakeholder Engagement Navigator webtool is a user-centered, interactive webtool suitable for use by researchers seeking guidance on appropriate stakeholder engagement methods for clinical and translational research projects.

Anxiety related to genetic testing for alpha-1 antitrypsin deficiency and cystic fibrosis in COPD and/or bronchiectasis patients.

OBJECTIVE: To describe the psychological reaction to information about diagnostic genetic testing for alpha-1 antitrypsin deficiency (Alpha-1) and cystic fibrosis (CF) in chronic obstructive pulmonary disease and/or bronchiectasis patients who were tested but did not know the results. METHODS: One hundred and three adults took the State-Trait Anxiety Inventory before and after a standardized educational intervention and responded to a questionnaire. RESULTS: Information about the limitations, risks and benefits of Alpha-1 and CF testing did not raise mean anxiety levels. Mean anxiety was slightly lower after the educational intervention than at baseline (mean pretest score 35.0, posttest score 33.7; p < 0.05). Participants whose physician preinformed them of genetic testing had slightly higher mean anxiety than other participants, both before and after the intervention, but scores were comparable to those in a normative sample of general medical and surgical patients. CONCLUSIONS: Disclosure of information regarding Alpha-1 and CF testing appears to be potentially acceptable to patients and unlikely to prevent clinicians from conducting useful diagnostic procedures. This study is a step in alleviating concerns about raising issues related to genetic testing for Alpha-1 and CF in chronic obstructive pulmonary disease patients during the informed consent process.

Translating Biobank Science into Patient-Centered Language.

INTRODUCTION: This project used Boot Camp Translation (BCT) to translate the complex medical jargon of biobanking into locally relevant evidence-based messages and materials to support increased knowledge and understanding in the local community. METHODS: Biobank BCT was a partnership of 16 community members and 5 academic researchers. The partnership met for 8 months. RESULTS: The partnership developed five main and seven submessages to assist patients and community members in making an informed decision about enrollment in a biobank. DISCUSSION: The resulting messages balance an individual's right to privacy and choice, while encouraging participation for the greater good.

Cannabis use disorder and male sex predict medical cannabis card status in a sample of high risk adolescents.

OBJECTIVE: To examine if a substance use disorder (SUD), especially cannabis use disorder in adolescence, predicts future medical cannabis card status among high-risk youth. METHODS: Data collection occurred in Denver and San Diego. We recruited adolescents, with or at high risk for SUD and conduct problems (hereafter probands) and their siblings (n=654). Baseline (Wave 1) assessments took place between 1999 and 2008, and follow-up (Wave 2) took place between 2010 and 2013. In initial bivariate analyses, we examined whether baseline DSM-IV cannabis abuse/dependence (along with other potential predictors) was associated with possessing a medical cannabis card in young adulthood (Wave 2). Significant predictors were then included in a multiple binomial regression. Self-reported general physical health was also evaluated at both time points. Finally, within Wave 2, we tested whether card status was associated with concurrent substance dependence. RESULTS: About 16% of the sample self-reported having a medical cannabis card at follow-up. Though bivariate analyses demonstrated that multiple predictors were significantly associated with Wave 2 card status, in our multiple binomial regression only cannabis abuse/dependence and male sex remained significant. At Wave 2, those with a medical cannabis card were significantly more likely to endorse criteria for concurrent cannabis dependence. There was no significant difference in self-reported general physical health. CONCLUSIONS: Cannabis abuse/dependence and male sex positively predicted future medical cannabis card holder status among a sample of high risk adolescents. Physicians conducting evaluations for medical cannabis cards should carefully evaluate and consider past and concurrent cannabis addiction.

Adolescents with substance use disorder and assent/consent: Empirical data on understanding biobank risks in genomic research.

OBJECTIVE: This study assessed whether a customized disclosure form increases understanding for adolescents with substance use disorder (SUD) when compared to a standard disclosure for genomic addiction research. METHOD: We gathered empirical data from adolescents with SUD, family members, former patients followed since adolescence, and community counterparts. The study was conducted in four stages. Stage 1: national experts (n=32) identified current, future, speculative risks of broadly shared biobanks. Stage 2 assessed participants' (n=181) understanding of current risks as a prerequisite for rating saliency of risks via a Visual Analog Scale. Salient risks were incorporated into a customized disclosure form. Stage 3 compared the understanding of customized disclosure by participants (n=165) at baseline; all groups scored comparably. Stage 4 conducted a direct comparison of the standard disclosure to standard disclosure plus customized disclosure (n=195). Independent t-tests compared understanding in those receiving the standard disclosure to standard disclosure plus customized disclosure within 6 groups. RESULTS: The customized disclosure significantly improved understanding in adolescent patients (p=0.002) and parents of patients (p=0.006) to the level of their counterparts. The customized disclosure also significantly improved understanding in siblings of former patients (p=0.034). Understanding of standard disclosure in patients versus controls was significantly different (p=0.005). The groups receiving the customized disclosure scored significantly higher. Understanding of the standard disclosure plus customized disclosure in patients versus controls was not significantly different. CONCLUSION: Adolescents with addictions understand the risks of participating in genomic addiction research as well as their community counterparts when information provided is salient to them.

What adolescents enrolled in genomic addiction research want to know about conflicts of interest.

BACKGROUND: Perspectives of adolescent research participants regarding conflicts of interest (COIs) and their impact on trust in researchers have not been studied. This study evaluates views of adolescent patients in treatment for substance and conduct problems compared to controls enrolled in genomic addiction research. METHODS: Participants included 273 (190 patients, 83 controls) adolescents. Participants consented or assented (with parental consent) to have their genomic information deposited in a NIH biobank that shares information globally with qualified investigators. As part of that study, participants completed a COI survey. Endorsement of each COI item was analyzed with multiple logistic regressions, evaluating group, age, sex, ethnicity, and highest grade completed. RESULTS: Patients and controls differed in gender, ethnicity and highest grade completed. In response to the survey, 38.4% of patients and 25.3% of controls "want to know" and 35.3% of patients and 37.3% of controls "might want to know" about COIs. Males were less likely to want/might want disclosure about COIs. Older patients were more likely to want disclosure about financial interests; patients were more likely to want disclosure about possible treatments; males were more likely to want information about monetary gains. Both groups requested between 1 paragraph and 1 page of information. Disclosure of COIs did not impact trust for most participants. CONCLUSION: Adolescent patients and controls in this study want comparable information for disclosure of COIs including monetary gains, salary, publications, grants, and professional awards. Notably, the majority of patients and controls report that disclosure will not undermine trust in researchers.

Adolescent perspectives on the return of individual results in genomic addiction research.

This study surveyed all adolescents who were enrolled in behavioral genomic research and provided DNA to a biobank, including 320 patients undergoing treatment for substance and conduct problems (SCPs) and 109 non-SCP controls. Participants selected from three options on the return of individual genomic results (RIR) and rated eight methods of re-contact. Most individuals with SCPs (77.8%) and non-SCP controls (72.5%) wanted RIR involving health or behavioral implications. The majority of individuals with SCPs (67.2%) and non-SCP controls (69.7%) indicated that phone re-contact was 'best', with e-mail (22.5% SCPs, 33.9% non-SCPs) and social networking websites (21.3% SCPs, 20.2% non-SCPs) being viable options. These results suggest a layered approach for RIR: phone calls, followed by e-mails and a secure message to a social networking account. Data from this special and vulnerable population, which includes youth involved in the criminal justice system and substantial minority participation, bring an essential and missing perspective to the discussion of RIR.