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1.  How behavioral economics can help to avoid ‘The last mile problem’ in whole genome sequencing 
Genome Medicine  2015;7(1):3.
Editorial summary
Failure to consider lessons from behavioral economics in the case of whole genome sequencing may cause us to run into the ‘last mile problem’ - the failure to integrate newly developed technology, on which billions of dollars have been invested, into society in a way that improves human behavior and decision-making.
doi:10.1186/s13073-015-0132-8
PMCID: PMC4302430  PMID: 25614766
2.  Experiences and Attitudes of Genome Investigators Regarding Return of Individual Genetic Test Results 
Purpose
Whether and how to return individual genetic results to study participants is among the most contentious policy issues in contemporary genomic research.
Methods
We surveyed corresponding authors of genome-wide association studies (GWAS), identified through the National Human Genome Research Institute's Catalog of Published GWAS, to describe the experiences and attitudes of these stakeholders.
Results
Of 357 corresponding authors, 200 (56%) responded. One hundred twenty-six (63%) had been responsible for primary data and sample collection, whereas 74 (37%) had performed secondary analyses. Only 7 (4%) had returned individual results within their index GWAS. Most (69%) believed that return of results to individual participants was warranted under at least some circumstances. Most respondents identified a desire to benefit participants's health (63%) and respect for participants's; desires for information (57%) as major motivations for returning results. Most also identified uncertain clinical utility (76%), the possibility that participants will misunderstand results (74%), the potential for emotional harm (61%), the need to ensure access to trained clinicians (59%), and the potential for loss of confidentiality (51%) as major barriers to return.
Conclusion
Investigators have limited experience returning individual results from genome-scale research, yet most are motivated to do so in at least some circumstances.
doi:10.1038/gim.2013.58
PMCID: PMC4143384  PMID: 23639901
3.  Social and behavioral research in genomic sequencing: approaches from the Clinical Sequencing Exploratory Research Consortium Outcomes and Measures Working Group 
The routine use of genomic sequencing in clinical medicine has the potential to dramatically alter patient care and medical outcomes. To fully understand the psychosocial and behavioral impact of sequencing integration into clinical practice, it is imperative that we identify the factors that influence sequencing-related decision making and patient outcomes. In an effort to develop a collaborative and conceptually grounded approach to studying sequencing adoption, members of the National Human Genome Research Institute's Clinical Sequencing Exploratory Research Consortium formed the Outcomes and Measures Working Group. Here we highlight the priority areas of investigation and psychosocial and behavioral outcomes identified by the Working Group. We also review some of the anticipated challenges to measurement in social and behavioral research related to genomic sequencing; opportunities for instrument development; and the importance of qualitative, quantitative, and mixed-method approaches. This work represents the early, shared efforts of multiple research teams as we strive to understand individuals' experiences with genomic sequencing. The resulting body of knowledge will guide recommendations for the optimal use of sequencing in clinical practice.
doi:10.1038/gim.2014.26
PMCID: PMC4163120  PMID: 24625446
behavior; genome sequencing; measures; outcomes; psychosocial
4.  Obtaining informed consent for clinical tumor and germline exome sequencing of newly diagnosed childhood cancer patients 
Genome Medicine  2014;6(9):69.
Background
Effectively educating families about the risks and benefits of genomic tests such as whole exome sequencing (WES) offers numerous challenges, including the complexity of test results and potential loss of privacy. Research on best practices for obtaining informed consent (IC) in a variety of clinical settings is needed. The BASIC3 study of clinical tumor and germline WES in an ethnically diverse cohort of newly diagnosed pediatric cancer patients offers the opportunity to study the IC process in the setting of critical illness. We report on our experience for the first 100 families enrolled, including study participation rates, reasons for declining enrollment, assessment of clinical and demographic factors that might impact study enrollment, and preferences of parents for participation in optional genomics study procedures.
Methods
A specifically trained IC team offered study enrollment to parents of eligible children for procedures including clinical tumor and germline WES with results deposited in the medical record and disclosure of both diagnostic and incidental results to the family. Optional study procedures were also offered, such as receiving recessive carrier status and deposition of data into research databases. Stated reasons for declining participation were recorded. Clinical and demographic data were collected and comparisons made between enrolled and non-enrolled patients.
Results
Over 15 months, 100 of 121 (83%) eligible families elected to enroll in the study. No significant differences in enrollment were detected based on factors such as race, ethnicity, use of Spanish interpreters and Spanish consent forms, and tumor features (central nervous system versus non-central nervous system, availability of tumor for WES). The most common reason provided for declining enrollment (10% of families) was being overwhelmed by the new cancer diagnosis. Risks specific to clinical genomics, such as privacy concerns, were less commonly reported (5.5%). More than 85% of parents consented to each of the optional study procedures.
Conclusions
An IC process was developed that utilizes a specialized IC team, active communication with the oncology team, and an emphasis on scheduling flexibility. Most parents were willing to participate in a clinical germline and tumor WES study as well as optional procedures such as genomic data sharing independent of race, ethnicity or language spoken.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-014-0069-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13073-014-0069-3
PMCID: PMC4195891  PMID: 25317207
5.  Open Access Data Sharing in Genomic Research 
Genes  2014;5(3):739-747.
The current emphasis on broad sharing of human genomic data generated in research in order to maximize utility and public benefit is a significant legacy of the Human Genome Project. Concerns about privacy and discrimination have led to policy responses that restrict access to genomic data as the means for protecting research participants. Our research and experience show, however, that a considerable number of research participants agree to open access sharing of their genomic data when given the choice. General policies that limit access to all genomic data fail to respect the autonomy of these participants and, at the same time, unnecessarily limit the utility of the data. We advocate instead a more balanced approach that allows for individual choice and encourages informed decision making, while protecting against the misuse of genomic data through enhanced legislation.
doi:10.3390/genes5030739
PMCID: PMC4198928  PMID: 25178093
data sharing; genomics; privacy; genetic discrimination; open access database
7.  Perspectives On Human Microbiome Research Ethics 
Study of ethical, legal, and social implications (ELSI) of human microbiome research has been integral to the Human Microbiome Project (HMP). This study explores core ELSI issues that arose during the first phase of the HMP from the perspective of individuals involved in the research. We conducted semi-structured in-depth interviews with investigators and NIH employees (“investigators”) involved in the HMP, and with individuals recruited to participate in the HMP Healthy Cohort Study at Baylor College of Medicine (“recruits”). We report findings related to three major ELSI issues: informed consent, data sharing, and return of results. Our findings demonstrate that investigators and recruits were similarly sensitive to these issues yet generally comfortable with study design in light of current knowledge about the microbiome.
doi:10.1525/jer.2012.7.3.1
PMCID: PMC4065416  PMID: 22850139
ethics; policy; research; human micro-biome; data sharing; informed consent; return of results; qualitative research
8.  Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy 
The New England journal of medicine  2010;362(13):1181-1191.
BACKGROUND
Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot–Marie–Tooth disease.
METHODS
We identified a family with a recessive form of Charcot–Marie–Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members.
RESULTS
We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome.
CONCLUSIONS
As shown in this study of a family with Charcot–Marie–Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.
doi:10.1056/NEJMoa0908094
PMCID: PMC4036802  PMID: 20220177
10.  Investigators’ Perspectives on Translating Human Microbiome Research into Clinical Practice 
Public health genomics  2013;16(3):127-133.
Background
Human microbiome research has the potential to transform the practice of medicine, fundamentally shifting the ways in which we think not only about human health, illness, and disease, but also about clinical practice and public health interventions. Drawing from a larger qualitative study on ethical, legal, and social dimensions of human microbiome research, in this article we document perspectives related to the translation of human microbiome research into clinical practice, focusing particularly on implications for health, illness, and disease.
Methods
We conducted 60 in-depth, semi-structured interviews (2009–2010) with 63 researchers and National Institutes of Health project leaders (“investigators”) involved with human microbiome research. Interviews explored a range of ethical, legal, and social implications of human microbiome research, including investigators’ perspectives on potential strategies for translating findings to clinical practice. Using thematic content analysis, we identified and analyzed emergent themes and patterns.
Results
We identified three themes: (1) Investigators’ general perspectives on the clinical utility of human microbiome research, (2) Investigators’ perspectives on antibiotic use, overuse, and misuse, and (3) Investigators’ perspectives concerning future challenges of translating data to clinical practice.
Conclusion
The issues discussed by investigators concerning the clinical significance of human microbiome research, including embracing a new paradigm of health and disease, the importance of microbial communities, and clinical utility, will be of critical importance as this research moves forward.
doi:10.1159/000350308
PMCID: PMC3760223  PMID: 23615375
human microbiome; translational genomic research; clinical genomics
11.  Participants’ recall and understanding of genomic research and large-scale data sharing 
As genomic researchers are urged to openly share generated sequence data with other researchers, it is important to examine the utility of informed consent documents and processes, particularly as these relate to participants’ engagement with and recall of the information presented to them, their objective or subjective understanding of the key elements of genomic research (e.g., data sharing), as well as how these factors influence or mediate the decisions they make. We conducted a randomized trial of three experimental informed consent documents (ICDs) with participants (n = 229) being recruited to genomic research studies; each document afforded varying control over breadth of release of genetic information. Recall and understanding, their impact on data sharing decisions, and comfort in decision making were assessed in a follow-up structured interview. Over 25% did not remember signing an ICD to participate in a genomic study, and the majority (54%) could not correctly identify with whom they had agreed to share their genomic data. However, participants felt that they understood enough to make an informed decision, and lack of recall did not impact final data sharing decisions or satisfaction with participation. These findings raise questions about the types of information participants need in order to provide valid informed consent, and whether subjective understanding and comfort with decision making are sufficient to satisfy the ethical principle of respect for persons.
doi:10.1525/jer.2013.8.4.42
PMCID: PMC3995160  PMID: 24169421
data sharing; genome research; informed consent; understanding; participant perspectives
12.  The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine 
Trials  2014;15:85.
Background
Whole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care.
Methods/Design
This pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients’ genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes, behaviors and outcomes of physician and patient participants at multiple time points before and after the disclosure of these results.
Discussion
The impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine will evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies.
Trial registration
ClinicalTrials.gov identifier NCT01736566
doi:10.1186/1745-6215-15-85
PMCID: PMC4113228  PMID: 24645908
Whole genome sequencing; Genome report; Genomic medicine; Translational genomics; Primary care; Cardiomyopathy genetics
13.  ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing 
In clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing, which emphasized the importance of disclosing the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. We recommend that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the ‘normal’ of tumor-normal subtractive analyses in all subjects, irrespective of age, but excluding fetal samples. We recognize that there are insufficient data on clinical utility to fully support these recommendations and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.
doi:10.1038/gim.2013.73
PMCID: PMC3727274  PMID: 23788249
secondary findings; incidental findings; genome; genomic medicine; personalized medicine; whole-exome; whole-genome; sequencing
14.  Reflections on the Cost of "Low-Cost" Whole Genome Sequencing: Framing the Health Policy Debate 
PLoS Biology  2013;11(11):e1001699.
The future clinical applications of whole genome sequencing come with speculation and enthusiasm but require careful consideration of the true system costs and health benefits of the clinical uses of this exciting technology.
Summary
The cost of whole genome sequencing is dropping rapidly. There has been a great deal of enthusiasm about the potential for this technological advance to transform clinical care. Given the interest and significant investment in genomics, this seems an ideal time to consider what the evidence tells us about potential benefits and harms, particularly in the context of health care policy. The scale and pace of adoption of this powerful new technology should be driven by clinical need, clinical evidence, and a commitment to put patients at the centre of health care policy.
doi:10.1371/journal.pbio.1001699
PMCID: PMC3818164  PMID: 24223516
15.  Returning genetic research results: study type matters 
Personalized medicine  2013;10(1):27-34.
Aim
The return of individual genetic research results has been identified as one of the most pressing ethical challenges warranting immediate policy attention. We explored the practices and perspectives of genome-wide association studies (GWAS) investigators on this topic.
Materials & methods
Corresponding authors of published GWAS were invited to participate in a semistructured interview. Interviews (n = 35) were transcribed and analyzed using conventional content analysis.
Results
Most investigators had not returned GWAS results. Several had experience returning results in the context of linkage/family studies, and many felt that it will become a larger issue in whole-genome/-exome sequencing.
Conclusions
Research context and nature of the study are important considerations in the decision to return results. More nuanced ethical guidelines should take these contextual factors into account.
doi:10.2217/pme.12.109
PMCID: PMC3783351  PMID: 24077424
ethics; genome-wide association; genomics; policy; return of results; whole-genome sequencing
16.  The legal risks of returning results of genomics research 
Published guidelines suggest that research results and incidental findings should be offered to study participants under some circumstances. Although some have argued against the return of results in research, many cite an emerging consensus that there is an ethical obligation to return at least some results; the debate quickly turns to issues of mechanics (e.g., which results? who discloses? for how long does the obligation exist?). Although commentators are careful to distinguish this as an ethical rather than legal obligation, we worry that return of results may unjustifiably become standard of care based on this growing “consensus,” which could quickly lead to a legal (negligence-based) duty to offer and return individualized genetic research results. We caution against this and argue in this essay that the debate to date has failed to give adequate weight to a number of fundamental ethical and policy issues that should undergird policy on return of research results in the first instance, many of which go to the fundamental differences between research and clinical care. We confine our comments to research using data from large biobanks, the topic of the guidelines proposed in this symposium issue.
doi:10.1038/gim.2012.10
PMCID: PMC3779603  PMID: 22323070
biobanking; ethics; genetics; law; policy; return of results
18.  Research Results: Preserving Newborn Blood Samples 
Science translational medicine  2012;4(159):159cm12.
doi:10.1126/scitranslmed.3004474
PMCID: PMC3763707  PMID: 23136040
19.  Exploring Concordance and Discordance for Return of Incidental Findings from Clinical Sequencing 
Purpose
To explore specific conditions and types of genetic variants that specialists in genetics recommend should be returned as incidental findings in clinical sequencing.
Methods
Sixteen specialists in clinical genetics and/or molecular medicine selected variants in 99 common conditions to return to the ordering physician if discovered incidentally through whole genome sequencing. For most conditions, the specialists independently considered 3 molecular scenarios for both adults and minor children: a known pathogenic mutation, a truncating variant presumed pathogenic (where other truncating variants were known to be pathogenic), or a missense variant predicted in silico to be pathogenic.
Results
On average, for adults and children respectively, each specialist selected 83.5 and 79.0 conditions or genes out of 99 in the known pathogenic mutation categories, 57.0 and 53.5 out of 72 in the truncating variant categories, and 33.4 and 29.7 out of 72 in the missense variant categories. Concordance in favor of disclosure within the adult/known pathogenic mutation category was 100% for 21 conditions or genes and 80% or higher for 64 conditions or genes.
Conclusion
Specialists were highly concordant for the return of findings in 64 conditions or genes if discovered incidentally during whole exome or whole genome sequencing.
doi:10.1038/gim.2012.21
PMCID: PMC3763716  PMID: 22422049
whole genome sequencing; incidental findings
21.  Policy Uncertainty, Sequencing, and Cell Lines 
G3: Genes|Genomes|Genetics  2013;3(8):1205-1207.
doi:10.1534/g3.113.007435
PMCID: PMC3737160  PMID: 23926222
22.  Return of Individual Research Results from Genome-wide Association Studies: Experience of the Electronic Medical Records & Genomics (eMERGE) Network 
Purpose
Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors.
Methods
The Electronic Medical Records and GEnomics (eMERGE) network, which includes five biorepositories conducting genome-wide association studies, convened a Return of Results Oversight Committee (RROC) to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision-making.
Results
Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The RROC identified two sex chromosomal anomalies, Klinefelter Syndrome and Turner Syndrome, as well as homozygosity for Factor V Leiden, as findings that could warrant reporting. Views about returning HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of EMRs suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site).
Conclusion
The eMERGE experience reveals the complexity of return of results decision-making and provides a potential deliberative model for adoption in other collaborative contexts.
doi:10.1038/gim.2012.15
PMCID: PMC3723451  PMID: 22361898
Result return; biorepository; electronic medical records; deliberation; context
23.  Informed Consent in Research to Improve the Number and Quality of Deceased-Donor Organs 
Critical care medicine  2011;39(2):280-283.
Improving the management of potential organ donors in the ICU could meet an important public health goal by increasing the number and quality of transplantable organs. However, randomized clinical trials (RCTs) are needed to quantify the extent to which specific interventions might enhance organ recovery and outcomes among transplant recipients. Among several barriers to conducting such studies are the absence of guidelines for obtaining informed consent for such studies, and the fact that deceased organ donors are not covered by extant federal regulations governing oversight of research with human subjects. This paper explores the underexamined ethical issues that arise in the context of donor management studies, and provides ethical guidelines and suggested regulatory oversight mechanisms to enable such studies to be conducted ethically. We conclude that both the respect that is traditionally accorded to the prior wishes of the dead and the possibility of post-mortem harm support a role for surrogate consent of donors in such RCTs. Furthermore, although recipients will often be considered human subjects under federal regulations, several ethical arguments support waiving requirements for recipient consent in donor management RCTs. Finally, we suggest that new regulatory mechanisms, perhaps linked to existing regional and national organ donation and transplantation infrastructures, must be established to protect patients in donor management studies while limiting unnecessary barriers to the conduct of this important research.
doi:10.1097/CCM.0b013e3181feeb04
PMCID: PMC3717371  PMID: 20975549
informed consent; organ donation; transplantation; research ethics
24.  Incidental copy-number variants identified by routine genome testing in a clinical population 
Purpose
Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained.
Methods
Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed.
Results
In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients’ referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition.
Conclusion
Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient.
doi:10.1038/gim.2012.95
PMCID: PMC3705759  PMID: 22878507
copy-number variation; genetic load; genomic mutational load; incidentalome; structural variation; variants of unknown significance
25.  The Right to Ignore Genetic Risk in the Genomic Era - Prenatal testing for Huntington Disease as a paradigm 
During the last decade, the field of human genome research has gone through a phase of rapid discovery that has provided scientists and physicians with a wide variety of research tools that are applicable to important medical issues. We describe a case of familial Huntington disease (HD), where the proband at risk preferred not to know his disease status but wanted to know the status in his unborn child. Once we found the father to be negative, the case raised an important ethical question regarding the management of this as well as future pregnancies. This paper discusses the arguments for and against the right not to know of one’s carrier status, as well as professional obligations in the context of withholding unwanted information that may have direct implications not only for the patient himself but also for other family members. HD has been the gold standard for many other adult onset genetic diseases in terms of carrier testing guidelines. Hence, we feel it is time to revisit the issue of prenatal testing for HD and consider updating the current recommendations regarding the patient’s right to “genetic ignorance”, the right not to know genetic information.
doi:10.1002/ajmg.a.33432
PMCID: PMC3648842  PMID: 20583190
Huntington Disease; prenatal testing; guidelines; ethics

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