Publications by authors named "Katrina A B Goddard"

98 Publications

Cancer Health Assessments Reaching Many (CHARM): A clinical trial assessing a multimodal cancer genetics services delivery program and its impact on diverse populations.

Contemp Clin Trials 2021 May 11;106:106432. Epub 2021 May 11.

Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Ave, Portland, OR 97227, USA.

Advances in the application of genomic technologies in clinical care have the potential to increase existing healthcare disparities. Studies have consistently shown that only a fraction of eligible patients with a family history of cancer receive recommended cancer genetic counseling and subsequent genetic testing. Care delivery models using pre-test and post-test counseling are not scalable, which contributes to barriers in accessing genetics services. These barriers are even more pronounced for patients in historically underserved populations. We have designed a multimodal intervention to improve subsequent cancer surveillance, by improving the identification of patients at risk for familial cancer syndromes, reducing barriers to genetic counseling/testing, and increasing patient understanding of complex genetic results. We are evaluating this intervention in two large, integrated healthcare systems that serve diverse patient populations (NCT03426878). The primary outcome is the number of diagnostic (hereditary cancer syndrome) findings. We are examining the clinical and personal utility of streamlined pathways to genetic testing using electronic medical record data, surveys, and qualitative interviews. We will assess downstream care utilization of individuals receiving usual clinical care vs. genetic testing through the study. We will evaluate the impacts of a literacy-focused genetic counseling approach versus usual care genetic counseling on care utilization and participant understanding, satisfaction, and family communication. By recruiting participants belonging to historically underserved populations, this study is uniquely positioned to evaluate the potential of a novel genetics care delivery program to reduce care disparities.
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http://dx.doi.org/10.1016/j.cct.2021.106432DOI Listing
May 2021

Lessons learned about harmonizing survey measures for the CSER consortium.

J Clin Transl Sci 2020 Apr 24;4(6):537-546. Epub 2020 Apr 24.

Division of Ethics, Department of Medical Humanities and Ethics, Columbia University, New York, NY, USA.

Introduction: Implementation of genome-scale sequencing in clinical care has significant challenges: the technology is highly dimensional with many kinds of potential results, results interpretation and delivery require expertise and coordination across multiple medical specialties, clinical utility may be uncertain, and there may be broader familial or societal implications beyond the individual participant. Transdisciplinary consortia and collaborative team science are well poised to address these challenges. However, understanding the complex web of organizational, institutional, physical, environmental, technologic, and other political and societal factors that influence the effectiveness of consortia is understudied. We describe our experience working in the Clinical Sequencing Evidence-Generating Research (CSER) consortium, a multi-institutional translational genomics consortium.

Methods: A key aspect of the CSER consortium was the juxtaposition of site-specific measures with the need to identify consensus measures related to clinical utility and to create a core set of harmonized measures. During this harmonization process, we sought to minimize participant burden, accommodate project-specific choices, and use validated measures that allow data sharing.

Results: Identifying platforms to ensure swift communication between teams and management of materials and data were essential to our harmonization efforts. Funding agencies can help consortia by clarifying key study design elements across projects during the proposal preparation phase and by providing a framework for data sharing data across participating projects.

Conclusions: In summary, time and resources must be devoted to developing and implementing collaborative practices as preparatory work at the beginning of project timelines to improve the effectiveness of research consortia.
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http://dx.doi.org/10.1017/cts.2020.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057449PMC
April 2020

Adaptation and early implementation of the PREdiction model for gene mutations (PREMM™) for lynch syndrome risk assessment in a diverse population.

Fam Cancer 2021 Mar 23. Epub 2021 Mar 23.

Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.

Lynch syndrome (LS) is the most common inherited cause of colorectal and endometrial cancers. Identifying individuals at risk for LS without personal cancer history requires detailed collection and assessment of family health history. However, barriers exist to family health history collection, especially in historically underserved populations. To improve LS risk assessment in historically underserved populations, we adapted the provider-facing PREdiction Model for gene Mutations (PREMM™ model), a validated LS risk assessment model, into a patient-facing electronic application through an iterative development process involving expert and patient stakeholders. We report on preliminary findings based on the first 500 individuals exposed to the adapted application in a primary care population enriched for low-literacy and low-resource patients. Major adaptations to the PREMM™ provider module included reduction in reading level, addition of interactive literacy aids, incorporation of family history assessment for both maternal and paternal sides of the family, and inclusion of questions about individual relatives or small groups of relatives to reduce cognitive burden. In the first 500 individuals, 90% completed the PREMM™ independently; of those, 94% did so in 5 min or less (ranged from 0.2 to 48.8 min). The patient-facing application was able to accurately classify 84% of patients as having clinically significant or not clinically significant LS risk. Our preliminary results suggest that in this diverse study population, most participants were able to rapidly, accurately, and independently complete an interactive application collecting family health history assessment that accurately assessed for Lynch syndrome risk.
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http://dx.doi.org/10.1007/s10689-021-00243-3DOI Listing
March 2021

Improving reporting standards for polygenic scores in risk prediction studies.

Nature 2021 Mar 10;591(7849):211-219. Epub 2021 Mar 10.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.
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http://dx.doi.org/10.1038/s41586-021-03243-6DOI Listing
March 2021

Development and early implementation of an Accessible, Relational, Inclusive and Actionable approach to genetic counseling: The ARIA model.

Patient Educ Couns 2021 05 23;104(5):969-978. Epub 2020 Dec 23.

Department of Humanities and Social Sciences, University of California, San Francisco, 1450 3rd St., San Francisco, CA 94158, USA.

Objective: To describe the training and early implementation of the ARIA model of genetic counseling (Accessible, Relational, Inclusive, Actionable).

Methods: As part of the Cancer Health Assessments Reaching Many (CHARM) study, an interdisciplinary workgroup developed the ARIA curriculum and trained genetic counselors to return exome sequencing results using the ARIA model.

Curriculum: The ARIA curriculum includes didactic elements, discussion, readings, role plays, and observations of usual care genetic counseling sessions. The ARIA model provides the skills and strategies needed for genetic counseling to be accessible to all patients, regardless of prior knowledge or literacy level; involves appropriate psychological and social counseling without overwhelming the patient with information; and leaves the patient with clear and actionable next steps.

Conclusion: With sufficient training and practice, the ARIA model appears to be feasible, with promise for ensuring that genetic counselors' communication is accessible, relational, inclusive and actionable for the diverse patients participating in genomic medicine.

Practice Implications: ARIA offers a coherent set of principles and strategies for effective communication with patients of all literacy levels and outlines specific techniques to practice and incorporate these skills into routine practice. The ARIA model could be integrated into genetic counseling training programs and practice, making genetic counseling more accessible and meaningful for all patients.
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http://dx.doi.org/10.1016/j.pec.2020.12.017DOI Listing
May 2021

A decision aid for additional findings in genomic sequencing: Development and pilot testing.

Patient Educ Couns 2021 05 6;104(5):960-968. Epub 2020 Nov 6.

Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, USA; Northwest Permanente, Kaiser Permanente Northwest, Portland, USA. Electronic address:

Objective: To describe the development of a web-based, patient-facing decision aid to support patients and research participants to make an informed, values-based decision about whether to receive additional results from genomic sequencing.

Methods: We developed the decision aid following the multi-step process described in the International Patient Decision Aids Standards. This utilized literature review, focus groups, and alpha testing with research participants undergoing clinical genomic sequencing.

Results: The decision aid, the Optional Results Choice Aid (ORCA), includes a seven-question "values clarification exercise," illustrative patient quotes, and summative guidance for the user. The decision aid was found to be highly readable, acceptable and relevant in alpha testing.

Conclusion: We developed a decision aid to support informed, values-based decision making for patients and research participants considering whether to receive additional results from genomic sequencing. ORCA is being implemented in the NHGRI-funded Cancer Health Assessment Reaching Many (CHARM) study, where we are measuring informed values-choice congruence.

Practice Implications: ORCA was designed to support patients and research participants to make an informed, values-based decision about whether to receive additional results from genomic sequencing.
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http://dx.doi.org/10.1016/j.pec.2020.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099937PMC
May 2021

Demonstrating 'respect for persons' in clinical research: findings from qualitative interviews with diverse genomics research participants.

J Med Ethics 2020 Oct 6. Epub 2020 Oct 6.

Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, Washington, USA.

The ethical principle of 'respect for persons' in clinical research has traditionally focused on protecting individuals' autonomy rights, but respect for participants also includes broader, although less well understood, ethical obligations to regard individuals' rights, needs, interests and feelings. However, there is little empirical evidence about how to effectively convey respect to potential and current participants. To fill this gap, we conducted exploratory, qualitative interviews with participants in a clinical genomics implementation study. We interviewed 40 participants in English (n=30) or Spanish (n=10) about their experiences with respect in the study and perceptions of how researchers in a hypothetical observational study could convey respect or a lack thereof. Most interviewees were female (93%), identified as Hispanic/Latino(a) (43%) or non-Hispanic white (38%), reported annual household income under US$60 000 (70%) and did not have a Bachelor's degree (65%); 30% had limited health literacy. We identified four key domains for demonstrating respect: (1) personal study team interactions, with an emphasis on empathy, appreciation and non-judgment; (2) study communication processes, including following up and sharing results with participants; (3) inclusion, particularly ensuring materials are understandable and procedures are accessible; and (4) consent and authorisation, including providing a neutral informed consent and keeping promises regarding privacy protections. While the experience of respect is inherently subjective, these findings highlight four key domains that may meaningfully demonstrate respect to potential and current research participants. Further empirical and normative work is needed to substantiate these domains and evaluate how best to incorporate them into the practice of research.
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http://dx.doi.org/10.1136/medethics-2020-106440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021602PMC
October 2020

Participant Reactions to a Literacy-Focused, Web-Based Informed Consent Approach for a Genomic Implementation Study.

AJOB Empir Bioeth 2021 Jan-Mar;12(1):1-11. Epub 2020 Sep 26.

Treuman Katz Center for Pediatric Bioethics, Seattle Children's Hospital and Research Institute, and Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.

Background: Clinical genomic implementation studies pose challenges for informed consent. Consent forms often include complex language and concepts, which can be a barrier to diverse enrollment, and these studies often blur traditional research-clinical boundaries. There is a move toward self-directed, web-based research enrollment, but more evidence is needed about how these enrollment approaches work in practice. In this study, we developed and evaluated a literacy-focused, web-based consent approach to support enrollment of diverse participants in an ongoing clinical genomic implementation study. : As part of the Cancer Health Assessments Reaching Many (CHARM) study, we developed a web-based consent approach that featured plain language, multimedia, and separate descriptions of clinical care and research activities. CHARM offered clinical exome sequencing to individuals at high risk of hereditary cancer. We interviewed CHARM participants about their reactions to the consent approach. We audio recorded, transcribed, and coded interviews using a deductively and inductively derived codebook. We reviewed coded excerpts as a team to identify overarching themes. : We conducted 32 interviews, including 12 (38%) in Spanish. Most (69%) enrolled without assistance from study staff, usually on a mobile phone. Those who completed enrollment in one day spent an average of 12 minutes on the consent portion. Interviewees found the information simple to read but comprehensive, were neutral to positive about the multimedia support, and identified increased access to testing in the study as the key difference from clinical care. : This study showed that interviewees found our literacy-focused, web-based consent approach acceptable; did not distinguish the consent materials from other online study processes; and valued getting access to testing in the study. Overall, conducting empirical bioethics research in an ongoing clinical trial was useful to demonstrate the acceptability of our novel consent approach but posed practical challenges.
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http://dx.doi.org/10.1080/23294515.2020.1823907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785634PMC
September 2020

Integrating stakeholder feedback in translational genomics research: an ethnographic analysis of a study protocol's evolution.

Genet Med 2020 06 24;22(6):1094-1101. Epub 2020 Feb 24.

Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Purpose: This study describes challenges faced while incorporating sometimes conflicting stakeholder feedback into study design and development of patient-facing materials for a translational genomics study aiming to reduce health disparities among diverse populations.

Methods: We conducted an ethnographic analysis of study documents including summaries of patient advisory committee meetings and interviews, reflective field notes written by study team members, and correspondence with our institutional review board (IRB). Through this analysis, we identified cross-cutting challenges for incorporating stakeholder feedback into development of our recruitment, risk assessment, and informed consent processes and materials.

Results: Our analysis revealed three key challenges: (1) balancing precision and simplicity in the design of study materials, (2) providing clinical care within the research context, and (3) emphasizing potential study benefits versus risks and limitations.

Conclusions: While involving patient stakeholders in study design and materials development can increase inclusivity and responsiveness to patient needs, patient feedback may conflict with that of content area experts on the research team and IRBs who are tasked with overseeing the research. Our analysis highlights the need for further empirical research about ethical challenges when incorporating patient feedback into study design, and for dialogue with genomic researchers and IRB representatives about these issues.
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http://dx.doi.org/10.1038/s41436-020-0763-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275883PMC
June 2020

Cost-Effectiveness of Risk-Stratified Colorectal Cancer Screening Based on Polygenic Risk: Current Status and Future Potential.

JNCI Cancer Spectr 2020 Feb 14;4(1):pkz086. Epub 2019 Oct 14.

See the Notes section for the full list of authors' affiliations.

Background: Although uniform colonoscopy screening reduces colorectal cancer (CRC) mortality, risk-based screening may be more efficient. We investigated whether CRC screening based on polygenic risk is a cost-effective alternative to current uniform screening, and if not, under what conditions it would be.

Methods: The MISCAN-Colon model was used to simulate a hypothetical cohort of US 40-year-olds. Uniform screening was modeled as colonoscopy screening at ages 50, 60, and 70 years. For risk-stratified screening, individuals underwent polygenic testing with current and potential future discriminatory performance (area under the receiver-operating curve [AUC] of 0.60 and 0.65-0.80, respectively). Polygenic testing results were used to create risk groups, for which colonoscopy screening was optimized by varying the start age (40-60 years), end age (70-85 years), and interval (1-20 years).

Results: With current discriminatory performance, optimal screening ranged from once-only colonoscopy at age 60 years for the lowest-risk group to six colonoscopies at ages 40-80 years for the highest-risk group. While maintaining the same health benefits, risk-stratified screening increased costs by $59 per person. Risk-stratified screening could become cost-effective if the AUC value would increase beyond 0.65, the price per polygenic test would drop to less than $141, or risk-stratified screening would lead to a 5% increase in screening participation.

Conclusions: Currently, CRC screening based on polygenic risk is unlikely to be cost-effective compared with uniform screening. This is expected to change with a greater than 0.05 increase in AUC value, a greater than 30% reduction in polygenic testing costs, or a greater than 5% increase in adherence with screening.
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http://dx.doi.org/10.1093/jncics/pkz086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988584PMC
February 2020

Recommended care and care adherence following a diagnosis of Lynch syndrome: a mixed-methods study.

Hered Cancer Clin Pract 2019 16;17:31. Epub 2019 Dec 16.

1Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR 97227 USA.

Background: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. This study assesses trends in diagnosis of LS and adherence to recommended LS-related care in a large integrated healthcare organization (~ 575,000 members).

Methods: Electronic medical record (EMR) data (1999-2015) were examined to identify patients with a diagnosis of LS. We examined their LS-associated care recommendations and adherence to these recommendations. Qualitative patient and provider interviews were conducted with the aim of identifying opportunities for improved care delivery.

Results: We identified 74 patients with a diagnosis of LS; 64% were diagnosed with a LS-related malignancy prior to their diagnosis of LS. The time to LS diagnosis following development of a LS-related cancer decreased over time: before 2009 11% of individuals received a diagnosis of LS within 1 year of developing a LS-related cancer compared to 83% after 2009 ( < 0.0001). Colonoscopy recommendations were documented in the EMR for almost all patients with LS (96%). Documentation of other recommendations for cancer surveillance was less commonly found. Overall, patient adherence to colonoscopy was high (M = 81.5%; SD = 32.7%), and adherence to other recommendations varied. To improve care coordination, patients and providers suggested providing automated reminder prompts for LS-related surveillance, adding a LS-specific diagnosis code, and providing guidelines for LS-related surveillance in the EMR.

Conclusions: We identified fewer than expected patients with LS in our large care system, indicating that there is still a diagnostic care gap. However, patients with LS were likely to receive and follow CRC surveillance recommendations. Recommendations for and adherence to extracolonic surveillance were variable. Improved care coordination and clearer documentation of the LS diagnosis is needed.
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http://dx.doi.org/10.1186/s13053-019-0130-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915941PMC
December 2019

The Genomic Medicine Integrative Research Framework: A Conceptual Framework for Conducting Genomic Medicine Research.

Am J Hum Genet 2019 06 16;104(6):1088-1096. Epub 2019 May 16.

Behavioural Science and Health Department, University College London, London, UK.

Conceptual frameworks are useful in research because they can highlight priority research domains, inform decisions about interventions, identify outcomes and factors to measure, and display how factors might relate to each other to generate and test hypotheses. Discovery, translational, and implementation research are all critical to the overall mission of genomic medicine and prevention, but they have yet to be organized into a unified conceptual framework. To fill this gap, our diverse team collaborated to develop the Genomic Medicine Integrative Research (GMIR) Framework, a simple but comprehensive tool to aid the genomics community in developing research questions, strategies, and measures and in integrating genomic medicine and prevention into clinical practice. Here we present the GMIR Framework and its development, along with examples of its use for research development, demonstrating how we applied it to select and harmonize measures for use across diverse genomic medicine implementation projects. Researchers can utilize the GMIR Framework for their own research, collaborative investigations, and clinical implementation efforts; clinicians can use it to establish and evaluate programs; and all stakeholders can use it to help allocate resources and make sure that the full complexity of etiology is included in research and program design, development, and evaluation.
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http://dx.doi.org/10.1016/j.ajhg.2019.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556906PMC
June 2019

Expert and lay perspectives on burden, risk, tolerability, and acceptability of clinical interventions for genetic disorders.

Genet Med 2019 11 26;21(11):2561-2568. Epub 2019 Apr 26.

Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.

Purpose: The Clinical Genome Resource (ClinGen) Actionability Working Group (AWG) developed a semiquantitative scoring metric to rate clinical actionability of genetic disorders and associated genes in four domains: (1) severity of the outcome, (2) likelihood of the outcome, (3) effectiveness of the intervention to prevent/minimize the outcome, and (4) nature of the intervention with respect to burden, risk, tolerability, and acceptability to the patient. This study aimed to assess whether nature of the intervention scores assigned by AWG experts reflected lay perceptions of intervention burden, risk, tolerability, and acceptability given the subjectivity of this domain.

Methods: In July 2017, a general population sample of 1344 adults completed the study. Each participant was asked to read 1 of 24 plain language medical intervention synopses and answer questions related to its burden, risk, tolerability, and acceptability. We conducted three multilevel mixed model analyses predicting the perceived burden, perceived risk, and perceived overall nature of the intervention.

Results: As AWG nature of the intervention scores increased, lay perceptions of intervention burden and risk decreased, and perceptions of tolerability and acceptability increased.

Conclusion: The findings show alignment between the ClinGen actionability scoring metric and lay perceptions of the nature of the intervention.
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http://dx.doi.org/10.1038/s41436-019-0524-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815237PMC
November 2019

Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting.

Fam Cancer 2019 07;18(3):317-325

Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA.

A subset of colorectal cancer (CRC) cases are attributable to Lynch syndrome (LS), a hereditary form of CRC. Effective evaluation for LS can be done on CRC tumors to guide diagnostic testing. Increased diagnosis of LS allows for surveillance and risk reduction, which can mitigate CRC-related burden and prevent cancer-related deaths. We evaluated participation in LS screening among newly diagnosed adult CRC patients. Some cases were referred for genetics evaluation prior to study recruitment (selective screening). Those not referred directly were randomized to the intervention or control (usual care) arms. Control cases were observed for one year, then given information about LS screening. Patients who declined participation were followed through the medical record. Of 601 cases of CRC, 194 (32%) enrolled in our study and were offered LS screening, 43 (7%) were followed as a control group, 148 (25%) declined participation and 216 (36%) were ineligible [63 (10%) of which received prior selective screening]. Six and nine cases of LS were identified through the intervention and selective screening groups, respectively. Overall, a higher proportion of PMS2 variants were identified in the intervention (3/6, 50%) versus selective screening groups (2/9, 22%) (not statistically significant). Eighty-eight percent and 23% of intervention and control patients, respectively, received LS screening. No control patients were found to have LS. Systems-based approaches are needed to ensure we fully identify LS cases. The proportion of LS cases from this program was 4% of newly diagnosed cases of CRC, similar to other programs.
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http://dx.doi.org/10.1007/s10689-019-00123-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685685PMC
July 2019

Correction: Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.

Genet Med 2019 May;21(5):1261-1262

Knight Diagnostic Laboratories, Oregon Health Science University, Portland, OR, USA.

The originally published version of this Article contained errors in Fig. 2. The numbers below the black arrowheads were incorrect; please see incorrect Figure in associated Correction. These errors have now been corrected in the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-019-0440-2DOI Listing
May 2019

A case for expanding carrier testing to include actionable X-linked disorders.

Clin Case Rep 2018 Nov 19;6(11):2092-2095. Epub 2018 Sep 19.

Center for Health Research Kaiser Permanente Northwest Portland Oregon.

A research study utilizing whole-genome sequence analysis for preconception carrier screening provided a genome-first detection of a severe de novo Factor VIII mutation in a woman with implications for pregnancy management and life-saving interventions of her newborn son, and a challenge to the existing paradigm regarding carrier testing.
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http://dx.doi.org/10.1002/ccr3.1806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230667PMC
November 2018

Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen's Actionability Working Group.

Hum Mutat 2018 11;39(11):1677-1685

Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon.

The use of genome-scale sequencing allows for identification of genetic findings beyond the original indication for testing (secondary findings). The ClinGen Actionability Working Group's (AWG) protocol for evidence synthesis and semi-quantitative metric scoring evaluates four domains of clinical actionability for potential secondary findings: severity and likelihood of the outcome, and effectiveness and nature of the intervention. As of February 2018, the AWG has scored 127 genes associated with 78 disorders (up-to-date topics/scores are available at www.clinicalgenome.org). Scores across these disorders were assessed to compare genes/disorders recommended for return as secondary findings by the American College of Medical Genetics and Genomics (ACMG) with those not currently recommended. Disorders recommended by the ACMG scored higher on outcome-related domains (severity and likelihood), but not on intervention-related domains (effectiveness and nature of the intervention). Current practices indicate that return of secondary findings will expand beyond those currently recommended by the ACMG. The ClinGen AWG evidence reports and summary scores are not intended as classifications of actionability, rather they provide a resource to aid decision makers as they determine best practices regarding secondary findings. The ClinGen AWG is working with the ACMG Secondary Findings Committee to update future iterations of their secondary findings list.
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http://dx.doi.org/10.1002/humu.23631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211797PMC
November 2018

Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.

Genet Med 2019 05 5;21(5):1100-1110. Epub 2018 Oct 5.

Knight Diagnostic Laboratories, Oregon Health Science University, Portland, OR, USA.

Purpose: Clinical sequencing emerging in health care may result in secondary findings (SFs).

Methods: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions.

Results: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care.

Conclusion: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.
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http://dx.doi.org/10.1038/s41436-018-0308-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450774PMC
May 2019

The evolving landscape of expanded carrier screening: challenges and opportunities.

Genet Med 2019 04 24;21(4):790-797. Epub 2018 Sep 24.

Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.

Carrier screening allows individuals to learn their chance of passing on an autosomal or X-linked condition to their offspring. Initially introduced as single-disease, ancestry-based screening, technological advances now allow for the possibility of multi-disease, pan-ethnic carrier screening, which we refer to as "expanded carrier screening." There are numerous potential benefits to expanded carrier screening, including maximizing the opportunity for couples to make autonomous reproductive decisions, and efficiency and marginal additional costs of including more conditions if the test is already being offered. While numerous laboratories currently offer expanded carrier screening services, it is not yet commonly used in clinical practice, and there is a lack of consensus among experts about the service, including whether this should be offered to individuals and couples, whether this should be offered preconception or prenatally, and what conditions to include in screening programs. Challenges for expanded carrier screening programs include a lack of demand from the public, low prioritization by health systems, the potential for pressure to undergo screening, the possibility of disability-based discrimination, needed adaptations to pre- and post-test counseling, technical limitations, and the evolving technological and socio-political landscape.
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http://dx.doi.org/10.1038/s41436-018-0273-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752283PMC
April 2019

The Clinical Sequencing Evidence-Generating Research Consortium: Integrating Genomic Sequencing in Diverse and Medically Underserved Populations.

Am J Hum Genet 2018 09;103(3):319-327

Department of Biomedical Research, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.

The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. At least 60% of participants will be of non-European ancestry or from underserved settings, with the goal of diversifying the populations that are providing an evidence base for genomic medicine. Five of the six clinical projects are enrolling pediatric patients with various phenotypes. One of these five projects is also enrolling couples whose fetus has a structural anomaly, and the sixth project is enrolling adults at risk for hereditary cancer. The ongoing NHGRI intramural project has enrolled primarily healthy adults. Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. The findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings.
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http://dx.doi.org/10.1016/j.ajhg.2018.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128306PMC
September 2018

Approaches to carrier testing and results disclosure in translational genomics research: The clinical sequencing exploratory research consortium experience.

Mol Genet Genomic Med 2018 11 21;6(6):898-909. Epub 2018 Aug 21.

Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, Washington.

Background: Clinical genome and exome sequencing (CGES) is primarily used to address specific clinical concerns by detecting risk of future disease, clarifying diagnosis, or directing treatment. Additionally, CGES makes possible the disclosure of autosomal recessive and X-linked carrier results as additional secondary findings, and research about the impact of carrier results disclosure in this context is needed.

Methods: Representatives from 11 projects in the clinical sequencing exploratory research (CSER) consortium collected data from their projects using a structured survey. The survey focused on project characteristics, which variants were offered and/or disclosed to participants as carrier results, methods for carrier results disclosure, and project-specific outcomes. We recorded quantitative responses and report descriptive statistics with the aim of describing the variability in approaches to disclosing carrier results in translational genomics research projects.

Results: The proportion of participants with carrier results was related to the number of genes included, ranging from 3% (three genes) to 92% (4,600 genes). Between one and seven results were disclosed to those participants who received any positive result. Most projects offered participants choices about whether to receive some or all of the carrier results. There were a range of approaches to communicate results, and many projects used separate approaches for disclosing positive and negative results.

Conclusion: Future translational genomics research projects will need to make decisions regarding whether and how to disclose carrier results. The CSER consortium experience identifies approaches that balance potential participant interest while limiting impact on project resources.
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http://dx.doi.org/10.1002/mgg3.453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305639PMC
November 2018

Assessment of willingness to pay for expanded carrier screening among women and couples undergoing preconception carrier screening.

PLoS One 2018 18;13(7):e0200139. Epub 2018 Jul 18.

Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, United States of America.

Background: Expanded carrier screening can provide risk information for numerous conditions. Understanding how individuals undergoing preconception expanded carrier screening value this information is important. The NextGen study evaluated the use of genome sequencing for expanded carrier screening and reporting secondary findings, and we measured participants' willingness to pay for this approach to understand how it is valued by women and couples planning a pregnancy.

Methods: We assessed 277 participants' willingness to pay for genome sequencing reporting carrier results for 728 gene/condition pairs and results for 121 secondary findings. We explored the association between attitudes and demographic factors and willingness to pay for expanded carrier screening using genome sequencing and conducted interviews with 58 of these participants to probe the reasoning behind their preferences.

Results: Most participants were willing to pay for expanded carrier screening using genome sequencing. Willingness to pay was associated with income level and religiosity, but not risk status for a condition in the carrier panel. Participants willing to pay nothing or a small amount cited issues around financial resources, whereas those willing to pay higher amounts were motivated by "peace of mind" from carrier results.

Conclusion: Women and couples planning a pregnancy value genome sequencing. The potentially high out-of-pocket cost of this service could result in healthcare disparities, since maximum amounts that participants were willing to pay were higher than a typical copay and related to income.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200139PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051630PMC
January 2019

Returning negative results to individuals in a genomic screening program: lessons learned.

Genet Med 2019 02 6;21(2):409-416. Epub 2018 Jun 6.

Department of Social Medicine, University of North Carolina at, Chapel Hill, NC, USA.

Purpose: In genomics, the return of negative screening results for rare, medically actionable conditions in large unselected populations with low prior risk of disease is novel and may involve important and nuanced concerns for communicating their meaning. Recruitment may result in self-selection because of participants' personal or family history, changing the characteristics of the screened population and interpretation of both positive and negative findings; prior motivations may also affect responses to results.

Methods: Using data from GeneScreen, an exploratory adult screening project that targets 17 genes related to 11 medically actionable conditions, we address four questions: (1) Do participants self-select based on actual or perceived risk for one of the conditions? (2) Do participants understand negative results? (3) What are their psychosocial responses? (4) Are negative results related to changes in reported health-related behaviors?

Results: We found disproportionate enrollment of individuals at elevated prior risk for conditions being screened, and a need to improve communication about the nature of screening and meaning of negative screening results. Participants expressed no decision regret and did not report intention to change health-related behaviors.

Conclusion: This study illuminates critical challenges to overcome if genomic screening is to benefit the general population.
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http://dx.doi.org/10.1038/s41436-018-0061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281871PMC
February 2019

Patient and provider perspectives on adherence to and care coordination of lynch syndrome surveillance recommendations: findings from qualitative interviews.

Hered Cancer Clin Pract 2018 10;16:11. Epub 2018 May 10.

1Center for Health Research, Kaiser Permanente Northwest, Portland, OR USA.

Background: Patients with a genetic variant associated with Lynch syndrome (LS) are recommended to undergo frequent and repeated cancer surveillance activities to minimize cancer-related morbidity and mortality. Little is known about how patients and primary care providers (PCPs) track and manage these recommendations. We conducted a small exploratory study of patient and PCP experiences with recommended LS surveillance activities and communication with family members in an integrated health care system.

Methods: We used in-depth interviews with patients and providers to understand how surveillance is coordinated and monitored following confirmation of LS. We recruited patients with a range of ages/gender, and providers with at least at least one patient with a molecular diagnosis of LS. All interviews were recorded, transcribed, and content analyzed by a trained qualitative methodologist.

Results: Twenty-two interviews were completed with 12 patients and 10 providers. Most patients (10) had detailed knowledge of surveillance recommendations, but were less sure of time intervals. While all patients reported receiving initial education about their surveillance recommendations from a genetic counselor, seven did not follow-up with a genetic counselor in subsequent years. A third of patients described taking sole responsibility for managing their LS surveillance care. Lack of routine communication from the health system (e.g., prompts for surveillance activities), and provider engagement were surveillance barriers. PCPs were generally aware of LS, but had limited familiarity with surveillance recommendations. Most PCPs (7) viewed LS as rare and relied on patient and specialist expertise and support. Providers typically had 1 patient with LS in a panel of 1800 patients overall. Providers felt strongly that management of LS should be coordinated by a dedicated team of specialists. Most patients (92%) had at least one family member that sought LS testing, and common barriers for family members included lack of insurance, affordability, and fear of result.

Conclusion: The maximal benefits of screening for confirmation of LS will only be realized with adherence to recommended preventive care. Important factors to ensure patients receive recommended LS care include a comprehensive and coordinated monitoring program that includes reminder prompts, and increased PCP education of LS and associated surveillance recommendations.
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http://dx.doi.org/10.1186/s13053-018-0090-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946437PMC
May 2018

Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory.

Am J Hum Genet 2018 06 10;102(6):1078-1089. Epub 2018 May 10.

Department of Molecular and Medical Genetics, Knight Diagnostic Laboratories, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address:

Advances in sequencing technologies permit the analysis of a larger selection of genes for preconception carrier screening. The study was designed as a sequential carrier screen using genome sequencing to analyze 728 gene-disorder pairs for carrier and medically actionable conditions in 131 women and their partners (n = 71) who were planning a pregnancy. We report here on the clinical laboratory results from this expanded carrier screening program. Variants were filtered and classified using the latest American College of Medical Genetics and Genomics (ACMG) guideline; only pathogenic and likely pathogenic variants were confirmed by orthologous methods before being reported. Novel missense variants were classified as variants of uncertain significance. We reported 304 variants in 202 participants. Twelve carrier couples (12/71 couples tested) were identified for common conditions; eight were carriers for hereditary hemochromatosis. Although both known and novel variants were reported, 48% of all reported variants were missense. For novel splice-site variants, RNA-splicing assays were performed to aid in classification. We reported ten copy-number variants and five variants in non-coding regions. One novel variant was reported in F8, associated with hemophilia A; prenatal testing showed that the male fetus harbored this variant and the neonate suffered a life-threatening hemorrhage which was anticipated and appropriately managed. Moreover, 3% of participants had variants that were medically actionable. Compared with targeted mutation screening, genome sequencing improves the sensitivity of detecting clinically significant variants. While certain novel variant interpretation remains challenging, the ACMG guidelines are useful to classify variants in a healthy population.
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http://dx.doi.org/10.1016/j.ajhg.2018.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992121PMC
June 2018

Lessons Learned From A Study Of Genomics-Based Carrier Screening For Reproductive Decision Making.

Health Aff (Millwood) 2018 05;37(5):809-816

Katrina A. B. Goddard is associate director, research programs, at the Center for Health Research, Kaiser Permanente Northwest.

Genomics-based carrier screening is one of many opportunities to use genomic information to inform medical decision making, but clinicians, health care delivery systems, and payers need to determine whether to offer screening and how to do so in an efficient, ethical way. To shed light on this issue, we conducted a study in the period 2014-17 to inform the design of clinical screening programs and guide further health services research. Many of our results have been published elsewhere; this article summarizes the lessons we learned from that study and offers policy insights. Our experience can inform understanding of the potential impact of expanded carrier screening services on health system workflows and workforces-impacts that depend on the details of the screening approach. We found limited patient or health system harms from expanded screening. We also found that some patients valued the information they learned from the process. Future policy discussions should consider the value of offering such expanded carrier screening in health delivery systems with limited resources.
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http://dx.doi.org/10.1377/hlthaff.2017.1578DOI Listing
May 2018

Time Costs for Genetic Counseling in Preconception Carrier Screening with Genome Sequencing.

J Genet Couns 2018 08 8;27(4):823-833. Epub 2018 Feb 8.

Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.

Advances in technology and the promise of personalized health care are driving greater use of genome sequencing (GS) for a variety of clinical scenarios. As health systems consider adopting GS, they need to understand the impact of GS on the organization and cost of care. While research has documented a dramatic decrease in the cost of sequencing and interpreting GS, few studies have examined how GS impacts genetic counseling workloads. This study examined the time needed to provide genetic counseling for GS in the context of preconception carrier screening. Genetic counselors prospectively reported on the time spent in the results disclosure process with 107 study participants who were part of the NextGen study. We found that the median time for results disclosure was 64 min (ranged from 5 to 229 min). Preparation work was the most time-consuming activity. Qualitative data from journal entries, debrief interviews with genetic counselors, and detailed case conference notes provided information on factors influencing time for results disclosure and implications for practice. Results suggest that expanded carrier screening could require significant increases in genetic counseling time, unless we are able to generate new resources to reduce preparation work or develop other strategies such as the creation of new models to deliver this type of service.
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http://dx.doi.org/10.1007/s10897-017-0205-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061093PMC
August 2018

Anticipated responses of early adopter genetic specialists and nongenetic specialists to unsolicited genomic secondary findings.

Genet Med 2018 10 1;20(10):1186-1195. Epub 2018 Feb 1.

Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA.

Purpose: Secondary findings from genomic sequencing are becoming more common. We compared how health-care providers with and without specialized genetics training anticipated responding to different types of secondary findings.

Methods: Providers with genomic sequencing experience reviewed five secondary-findings reports and reported attitudes and potential clinical follow-up. Analyses compared genetic specialists and physicians without specialized genetics training, and examined how responses varied by secondary finding.

Results: Genetic specialists scored higher than other providers on four-point scales assessing understandings of reports (3.89 vs. 3.42, p = 0.0002), and lower on scales assessing reporting obligations (2.60 vs. 3.51, p < 0.0001) and burdens of responding (1.73 vs. 2.70, p < 0.0001). Nearly all attitudes differed between findings, although genetic specialists were more likely to assert that laboratories had no obligations when findings had less-established actionability (p < 0.0001 in interaction tests). The importance of reviewing personal and family histories, documenting findings, learning more about the variant, and recommending familial discussions also varied according to finding (all p < 0.0001).

Conclusion: Genetic specialists felt better prepared to respond to secondary findings than providers without specialized genetics training, but perceived fewer obligations for laboratories to report them, and the two groups anticipated similar clinical responses. Findings may inform development of targeted education and support.
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http://dx.doi.org/10.1038/gim.2017.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103906PMC
October 2018

Patient perspectives on the use of categories of conditions for decision making about genomic carrier screening results.

Am J Med Genet A 2018 02 18;176(2):376-385. Epub 2017 Dec 18.

Treuman Katz Center for Pediatric Bioethics, Seattle Children's Hospital and Research Institute, Seattle, Washington.

As expanded genome-scale carrier screening becomes increasingly prevalent, patients will face decisions about whether to receive results about a vast number of genetic conditions. Understanding patient preferences is important to meaningfully demonstrate the ethical goal of respect and support patient autonomy. We explore one possible way to elicit preferences by sorting conditions into categories, which may support patient decision making, but the extent to which categories are helpful is unknown. In the context of a randomized trial of genome sequencing for preconception carrier screening compared to usual care (single disease carrier testing), we interviewed 41 participants who had genome sequencing about their experience using a taxonomy of conditions to select categories of results to receive. We then conducted interviews with an additional 10 participants who were not randomized to genome sequencing, asking them about the taxonomy, their reasons for selecting categories, and alternative ways of presenting information about potential results to receive. Participants in both groups found the categories helpful and valued having a meaningful opportunity to choose which results to receive, regardless of whether they opted to receive all or only certain categories of results. Additionally, participants who received usual care highlighted preparedness as a primary motivation for receiving results, and they indicated that being presented with possible reasons for receiving or declining results for each category could be helpful. Our findings can be used to develop approaches, including the use of categories, to support patient choices in expanded carrier screening. Further research should evaluate and optimize these approaches.
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http://dx.doi.org/10.1002/ajmg.a.38583DOI Listing
February 2018

Online Education and e-Consent for GeneScreen, a Preventive Genomic Screening Study.

Public Health Genomics 2017 26;20(4):235-246. Epub 2017 Oct 26.

Department of Social Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Online study recruitment is increasingly popular, but we know little about the decision making that goes into joining studies in this manner. In GeneScreen, a genomic screening study that utilized online education and consent, we investigated participants' perceived ease when deciding to join and their understanding of key study features.

Methods: Individuals were recruited via mailings that directed them to a website where they could learn more about GeneScreen, consent to participate, and complete a survey.

Results: Participants found it easy to decide to join GeneScreen and had a good understanding of study features. Multiple regression analyses revealed that ease of deciding to join was related to confidence in one's genetic self-efficacy, limited concerns about genetic screening, trust in and lack of frustration using the website, and the ability to spend a limited time on the website. Understanding of study features was related to using the Internet more frequently and attaining more information about GeneScreen conditions.

Conclusions: The ease of deciding to join a genomic screening study and comprehension of its key features should be treated as different phenomena in research and practice. There is a need for a more nuanced understanding of how individuals respond to web-based consent information.
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http://dx.doi.org/10.1159/000481359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698149PMC
June 2018