Renee Robinson

Risk, Reward, and the Double-Edged Sword: Perspectives on Pharmacogenetic Research and Clinical Testing Among Alaska Native People

OBJECTIVESnPharmacogenetic research and clinical testing raise important concerns for individuals and communities, especially where past medical research and practice has perpetrated harm and cultivated distrust of health care systems and clinicians. We investigated perceptions of pharmacogenetics among Alaska Native (AN) people.nnnMETHODSnWe held four focus groups for 32 ANs in south central Alaska to elicit views about pharmacogenetics in general and for treatment of cardiovascular disease, breast cancer, depression, and nicotine addiction. We analyzed data for perceived risks and rewards of pharmacogenetics.nnnRESULTSnPotential risks of pharmacogenetics included health care rationing, misuse of information, and stigma to individuals and the AN community. Potential rewards included decreased care costs, improved outcomes, and community development. Participants also discussed 8 contingent conditions that could mitigate risks and increase pharmacogenetic acceptability.nnnCONCLUSIONSnAlaska Natives perceive pharmacogenetics as potentially benefitting and harming individuals, communities, and health systems, depending on methods and oversight. Researchers, clinicians, and administrators, especially in community-based clinic and health care systems serving minority populations, must address this double-edged sword to effectively conduct pharmacogenetics.

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX.

Objectives Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. Methods We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup’ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). Results We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (−1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Conclusion Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska.

Pharmacogenetic research in partnership with American Indian and Alaska Native communities

Pharmacogenetics is a subset of personalized medicine that applies knowledge about genetic variation in gene-drug pairs to help guide optimal dosing. There is a lack of data, however, about pharmacogenetic variation in underserved populations. One strategy for increasing participation of underserved populations in pharmacogenetic research is to include communities in the research process. We have established academic-community partnerships with American Indian and Alaska Native people living in Alaska and Montana to study pharmacogenetics. Key features of the partnership include community oversight of the project, research objectives that address community health priorities, and bidirectional learning that builds capacity in both the community and the research team. Engaging the community as coresearchers can help build trust to advance pharmacogenetic research objectives.

Engaging stakeholders to develop a depression management decision support tool in a tribal health system

AbstractPurposenSouthcentral Foundation, an Alaska Native tribal health organization, has had a depression screening program in primary care since 2001. Program monitoring identified gaps in antidepressant refills and patients’ follow-up with behavioral health services. With extensive stakeholder participation, we developed an electronic, patient-centered, depression-management decision support tool (DM-DST). Quality of life and other outcomes are being assessed in a separate study; this case study reports on the multi-year stakeholder engagement process.MethodsData sources included interviews with patients and providers from integrated primary care teams, notes from research meetings, steering committee meetings, and consultations with tribal health system leadership, human subjects review committees, providers, and software designers, and a pilot test of the DS-DMT with patients and providers. We analyzed these sources using qualitative methods to assess the impact of stakeholder input on project processes and outcomes.ResultsOne comprehensive, iPad-based tool was originally planned to facilitate discussions about depression management. Stakeholder input emphasized the role of family and cultural context of depression and management and improving the usability of the DM-DST. Stakeholder direction led us to split the DM-DST into: (1) a brief iPad-based tool to facilitate conversations between patients and providers during clinic visits; and (2) a complementary Web site that provides detailed information and allows patients flexibility and time to learn more about depression and share information and preferences with family and friends.ConclusionsStakeholder input across the project substantially modified the DM-DST to ensure cultural applicability to patients and providers and facilitate integration into clinics.

Estimating Cotinine Associations and a Saliva Cotinine Level to Identify Active Cigarette Smoking in Alaska Native Pregnant Women

Studies indicate nicotine metabolism varies by race and can change during pregnancy. Given high rates of tobacco use and limited studies among Alaska Native (AN) women, we estimated associations of saliva cotinine levels with cigarette use and second-hand smoke (SHS) exposure and estimated a saliva cotinine cutoff to distinguish smoking from non-smoking pregnant AN women. Using questionnaire data and saliva cotinine, we utilized multi-variable linear regression (nxa0=xa0370) to estimate cotinine associations with tobacco use, SHS exposure, demographic, and pregnancy-related factors. Additionally, we estimated an optimal saliva cotinine cutoff for indication of active cigarette use in AN pregnant women using receiver operating characteristic (ROC) curve analysis (nxa0=xa0377). Saliva cotinine significantly decreased with maternal age and significantly increased with cigarettes smoked per day, SHS exposure, and number of previous full term pregnancies. Using self-reported cigarette use in the past 7xa0days as indication of active smoking, the area under the ROC curve was 0.975 (95xa0% CI: 0.960–0.990). The point closest to 100xa0% specificity and sensitivity occurred with a cotinine concentration of 1.07xa0ng/mL, which corresponded to sensitivity of 94xa0% and specificity of 94xa0%. We recommend using a saliva cotinine cutoff of 1xa0ng/mL to distinguish active smoking in pregnant AN women. This cutoff is lower than used in other studies with pregnant women, most likely due to high prevalence of light or intermittent smoking in the AN population. Continued study of cotinine levels in diverse populations is needed.

Prenatal alcohol exposure among Alaska Native/American Indian infants.

Background Recent reports indicate a decline in rates of Fetal Alcohol Syndrome (FAS) among Alaska Native and American Indian (AN/AI) infants. Nevertheless, AN/AI infants remain disproportionately impacted by the effects of prenatal alcohol exposure. Methods AN/AI pregnant women in their 3rd trimester completed a questionnaire on demographic data and the amount and frequency of their alcohol consumption in the month prior to conception and during pregnancy. Differences across demographics and trimesters were tested with the Chi-square, Fishers exact or McNemars test as appropriate. Results Of the 125 participants, 56% (n=71) reported no alcohol consumption in the 1st through 3rd trimesters of pregnancy; 30% (n=38) of the 125 participants also reported no alcohol consumption in the month before pregnancy. Of the 43% (n=54) who reported consuming alcohol during pregnancy (1st, 2nd and/or 3rd trimester), most (35%) reported alcohol use only in the 1st trimester. Binge drinking in the 1st or 2nd trimester was reported amongst 20% (n=25) of participants with an additional 18% (n=29) reporting binge drinking in the month prior to pregnancy. Women who reported pre-conception binge drinking were significantly more likely to report binge drinking during their 1st trimester (p<0.0001) and 2nd trimester (p<0.0001). A history of tobacco use (p=0.0403) and cigarette smoking during pregnancy (p<0.0001) were also associated with binge drinking during pregnancy. Conclusion Among study participants, reported use of alcohol was primarily limited to pre-conception and the 1st trimester, with a dramatic decrease in the 2nd and 3rd trimesters. Prevention programmes, such as the Alaska FAS Prevention Project, may have contributed to observed decreases in the 2nd and 3rd trimesters. Additional study and focus on pre-conception, the 1st trimester and binge drinking, as well as tobacco use might augment Fetal Alcohol Spectrum Disorder prevention efforts.

P450 Pharmacogenetics in Indigenous North American Populations

Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Métis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without adequate representation in pharmacogenetic studies establishing genotype-phenotype relationships, Indigenous populations may not benefit fully from new innovations in precision medicine testing to tailor and improve the safety and efficacy of drug treatment, resulting in health care disparities. The purpose of this review is to summarize and evaluate what is currently known about cytochrome P450 genetic variation in Indigenous populations in North America and to highlight the importance of including these groups in future pharmacogenetic studies for implementation of personalized drug therapy.

Perceptions of pharmacogenetic research to guide tobacco cessation by patients, providers and leaders in a tribal healthcare setting

AIMnDescribe patients, providers and healthcare system leaders perceptions of pharmacogenetic research to guide tobacco cessation treatment in an American Indian/Alaska Native primary care setting.nnnMATERIALS & METHODSnThis qualitative study used semistructured interviews with 20 American Indian/Alaska Native current or former tobacco users, 12 healthcare providers and nine healthcare system leaders.nnnRESULTSnParticipants supported pharmacogenetic research to guide tobacco cessation treatment provided that a community-based participatory research approach be employed, research closely coordinate with existing tobacco cessation services and access to pharmacogenetic test results be restricted to providers involved in tobacco cessation.nnnCONCLUSIONnDespite a history of mistrust toward genetic research in tribal communities, participants expressed willingness to support pharmacogenetic research to guide tobacco cessation treatment.

Views on electronic cigarette use in tobacco screening and cessation in an Alaska Native healthcare setting

Background American Indian (AI) and Alaska Native (AN) communities confront some of the highest rates of tobacco use and its sequelae. Methods This formative research project sought to identify the perspectives of 41 stakeholders (community members receiving care within the healthcare system, primary care providers, and tribal healthcare system leaders) surrounding the use of pharmacogenetics toward tobacco cessation treatment in the setting of an AI/AN owned and operated health system in south central Alaska. Results Interviews were held with 20 adult AI/AN current and former tobacco users, 12 healthcare providers, and 9 tribal leaders. An emergent theme from data analysis was that current tobacco screening and cessation efforts lack information on electronic cigarette (e-cigarette) use. Perceptions of the use of e-cigarettes role in tobacco cessation varied. Conclusion Preventive screening for tobacco use and clinical cessation counseling should address e-cigarette use. Healthcare provider tobacco cessation messaging should similarly address e-cigarettes.Background American Indian (AI) and Alaska Native (AN) communities confront some of the highest rates of tobacco use and its sequelae. Methods This formative research project sought to identify the perspectives of 41 stakeholders (community members receiving care within the healthcare system, primary care providers, and tribal healthcare system leaders) surrounding the use of pharmacogenetics toward tobacco cessation treatment in the setting of an AI/AN owned and operated health system in south central Alaska. Results Interviews were held with 20 adult AI/AN current and former tobacco users, 12 healthcare providers, and 9 tribal leaders. An emergent theme from data analysis was that current tobacco screening and cessation efforts lack information on electronic cigarette (e-cigarette) use. Perceptions of the use of e-cigarettes role in tobacco cessation varied. Conclusion Preventive screening for tobacco use and clinical cessation counseling should address e-cigarette use. Healthcare provider tobacco cessation messaging should similarly address e-cigarettes.

Depression management interests among Alaska Native and American Indian adults in primary care

BACKGROUNDnDepression remains the second leading cause of disability worldwide. Symptoms of depression are expressed and experienced differently across cultural groups, impacting treatment decisions. Patient preferences predict service utilization, treatment selection and persistence, as well as health outcomes for medical and behavioral health conditions, including depression. We identified depression management preferences of Alaska Native and American Indian (AN/AI) people who receive care within a comprehensive, integrated, tribally owned and operated healthcare facility in Anchorage, Alaska.nnnMETHODSnAdult AN/AI patients who screened positive for depression (10 or greater on the Patient Health Questionnaire - 9 (PHQ-9)) completed a culturally-tailored decision-support tool to assess their depression management interests.nnnRESULTSnThe 125 eligible patients, who screened positive for depression, preferred counseling and medications to peer support groups, herbal remedies, and spiritual support. Those 18-39 years of age were more likely to prefer medications and less likely to prefer spirituality and peer support than those 40 years of age and older. Patients with moderate and severe depression were more likely to prefer exercise, healthy eating, and stress reduction than individuals with mild depression.nnnLIMITATIONSnWomen comprised 78% of the sample. Responses may not adequately represent the views of men.nnnCONCLUSIONSnCounseling and medications should consistently be made available earlier in the course of depression management. Patient interest in exercise, stress reduction, and healthy eating to manage depression, especially among those with moderate and severe depression, offers opportunity for additional collaboration in an integrated care setting.