Islet autoantibodies are predominantly measured by radioassay to facilitate risk assessment and diagnosis of type 1 diabetes. However, the reliance on radioactive components, large sample volumes and limited throughput renders radioassay testing costly and challenging. We developed a multiplex analysis platform based on antibody detection by agglutination-PCR (ADAP) for the sample-sparing measurement of GAD, IA-2 and insulin autoantibodies/antibodies in 1 μL serum. The assay was developed and validated in 7 distinct cohorts (n = 858) with the majority of the cohorts blinded prior to analysis. Measurements from the ADAP assay were compared to radioassay to determine correlation, concordance, agreement, clinical sensitivity and specificity. The average overall agreement between ADAP and radioassay was above 91%. The average clinical sensitivity and specificity were 96% and 97%. In the IASP 2018 workshop, ADAP achieved the highest sensitivity of all assays tested at 95% specificity (AS95) rating for GAD and IA-2 autoantibodies and top-tier performance for insulin autoantibodies. Furthermore, ADAP correctly identified 95% high-risk individuals with two or more autoantibodies by radioassay amongst 39 relatives of T1D patients tested. In conclusion, the new ADAP assay can reliably detect the three cardinal islet autoantibodies/antibodies in 1μL serum with high sensitivity. This novel assay may improve pediatric testing compliance and facilitate easier community-wide screening for islet autoantibodies.

There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments-approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

OBJECTIVE:This paper outlines the implementation of a comprehensive clinical pharmacogenomics (PGx) service within a pediatric teaching hospital and the integration of clinical decision support in the electronic health record (EHR).MATERIALS AND METHODS:An approach to clinical decision support for medication ordering and dispensing driven by documented PGx variant status in an EHR is described. A web-based platform was created to automatically generate a clinical report from either raw assay results or specified diplotypes, able to parse and combine haplotypes into an interpretation for each individual and compared to the reference lab call for accuracy.RESULTS:Clinical decision support rules built within an EHR provided guidance to providers for 31 patients (100%) who had actionable PGx variants and were written for interacting medications. A breakdown of the PGx alerts by practitioner service, and alert response for the initial cohort of patients tested is described. In 90% (355/394) of the cases, thiopurine methyltranferase genotyping was ordered pre-emptively.DISCUSSION:This paper outlines one approach to implementing a clinical PGx service in a pediatric teaching hospital that cares for a heterogeneous patient population. There is a focus on incorporation of PGx clinical decision support rules and a program to standardize report text within the electronic health record with subsequent exploration of clinician behavior in response to the alerts.CONCLUSION:The incorporation of PGx data at the time of prescribing and dispensing, if done correctly, has the potential to impact the incidence of adverse drug events, a significant cause of morbidity and mortality.

Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization's prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes.

Objectives: To understand opinions and perceptions on the state of information resources specifically targeted to genomics, and approaches to delivery in clinical practice.Methods: We conducted a survey of genomic content use and its clinical delivery from representatives across eight institutions in the electronic Medical Records and Genomics (eMERGE) network and two institutions in the Clinical Sequencing Exploratory Research (CSER) consortium in 2014.Results: Eleven responses representing distinct projects across ten sites showed heterogeneity in how content is being delivered, with provider-facing content primarily delivered via the electronic health record (EHR) (n=10), and paper/pamphlets as the leading mode for patient-facing content (n=9). There was general agreement (91%) that new content is needed for patients and providers specific to genomics, and that while aspects of this content could be shared across institutions there remain site-specific needs (73% in agreement).Conclusion: This work identifies a need for the improved access to and expansion of information resources to support genomic medicine, and opportunities for content developers and EHR vendors to partner with institutions to develop needed resources, and streamline their use - such as a central content site in multiple modalities while implementing approaches to allow for site-specific customization.

The landscape of pediatric research is becoming more complex. Contemporary research studies, and genome studies in particular, frequently involve a range of research activities. For example, the Clinical Sequencing Exploratory Research Consortium studies evaluate whether genomic testing can be useful in clinical settings.1Clinical Sequencing Exploratory Research (CSER). National Human Genome Research Institute, National Institutes of Health, 2013http://www.genome.gov/27546194Google Scholar These studies include the storage of biosamples for future research, observations about the way providers interact with results reported in electronic health records, and the contribution of data to national databases like ClinVar and the Database of Genotypes and Phenotypes (dbGaP).2dbGaP Bethesda MD: U.S. National Library of Medicine; 2014 [cited 2014 October 1]. http://www.ncbi.nlm.nih.gov/gap. Accessed October 1, 2014.Google Scholar, 3ClinVar Bethesda MD: U.S. National Library of Medicine, 2014 [cited 2014 October 1]. http://www.ncbi.nlm.nih.gov/clinvar/. Accessed October 1, 2014.Google Scholar Given this complexity, pediatric investigators and Institutional Review Boards (IRBs) working on research projects of this type may find it challenging to develop an appropriate plan for addressing consent when pediatric research participants reach adulthood. After all, the research activities that comprise a complex study frequently differ with respect to timing, the risk involved, and the opportunities for interaction between investigators and participants. Any plan to readdress consent when a participant reaches the age of majority must account for all of these considerations. In order to address this changing landscape, we provide a framework that genomics researchers and IRB members can use to address consent when enrolled children reach adulthood. Based on both ethical and regulatory perspectives, we argue that the importance of replacing parental permission with a young adult's own informed consent depends on the nature of the research activities that will take place following a participant's transition to adulthood. Research activities that either confer substantial risk, or provide opportunities to obtain consent through ongoing contact, should be continued only if explicit informed consent is obtained from young adult participants. However, we argue that it is ethically permissible and consistent with current regulations to continue certain types of research activities under a waiver of participant consent, and that IRBs should use the full range of options provided by existing regulations. In making this argument, we work from the understanding that IRBs have significant latitude to interpret regulatory frameworks and policies in light of local priorities. We then apply this framework to a range of more specific questions, including how investigators leading genomic studies should manage the issues that arise when attempts to contact a young adult for consent are unsuccessful. Consider a hypothetical genomic research study in which pediatric research participants are taking part in a series of research activities. After children are enrolled with the permission of their parents, their genome sequence is analyzed to identify genetic targets to inform therapeutic interventions for a specific medical condition. Treatment for the medical condition is modified based on sequencing results and evaluated through frequent follow-up appointments over a 3-year period. Once this interventional stage is completed, the investigators intend to conduct additional analyses using both genomic data and other collected data. If they discover additional genomic results that might be clinically relevant to a participant, they intend to disclose these results to the family. They also intend to contact all participants and parents once a year to remind them they may receive genomic results in the future, to provide updates on the study, and to update participants' contact information. Consider 3 pediatric participants whose involvement in these research activities differed at the time of their transition to adulthood and the implications of these differences for the approach to contact and consent. The first participant is Anna. She enrolled when she was 10 years old and provided her assent to participate in the study. She completed the interventional portion when she was 13. When she reached the age of majority, the investigators were still analyzing her identified sample. They had remained in contact with her and her parents every year, and kept her contact information up-to-date. Now that Anna is a legal adult, do investigators need to obtain her consent to continue using her sample for research purposes, and before reviewing additional results that might be returned to her? Bryon, the second participant, was also 10 years old when he assented to enrollment. He completed the interventional portion when he was 13 years old and then moved with his parents to another state. When he turned 14, research coordinators tried unsuccessfully to update his contact information. By the time he reached the age of majority, it had been nearly 5 years since the study investigators had been in contact with him. Do the investigators need to attempt to contact Bryon before using his sample for further research? What should they do if they are unable to reach him? Do they need to de-identify or even destroy his data and samples? Christopher enrolled in and assented to study participation when he was 16 years of age. He was still an active participant in the interventional portion of the study when he reached the age of majority. Do the investigators need to obtain Christopher's consent in order to keep him enrolled in the interventional portion of the study? Even though all 3 adolescents participated in the same study, their involvement in the study when they became legal adults was quite different. These differences can affect both the feasibility of reaching a participant and the approaches to consent that might be appropriate. Studies often include research activities that differ in their implications for considering consent when participants reach the age of majority. First, they differ with respect to timing. Some research activities last only a few months and will have been completed at the time an adolescent reaches the age of majority. Others may continue indefinitely. Thus, depending on the age when the child enrolled, the activities that are ongoing when a participant reaches adulthood will vary. Second, the risks vary. Research activities that examine the effect of modifying clinical practice based on genomic test results may place participants at risk for physical harm. There is also a concern that providing genomic research results to participants may cause psychological harm,4Lam R.W. Bloch M. Jones B.D. Marcus A.M. Fox S. Amman W. et al.Psychiatric morbidity associated with early clinical diagnosis of Huntington disease in a predictive testing program.J Clin Psychiatry. 1988; 49: 444-447PubMed Google Scholar although this risk appears to be very low.5Green R.C. Roberts J.S. Cupples L.A. Relkin N.R. Whitehouse P.J. Brown T. et al.Disclosure of APOE genotype for risk of Alzheimer's disease.N Engl J Med. 2009; 361: 245-254Crossref PubMed Scopus (376) Google Scholar, 6Shalowitz D.I. Miller F.G. Communicating the results of clinical research to participants: attitudes, practices, and future directions.PLoS Med. 2008; 5: e91Crossref PubMed Scopus (171) Google Scholar The storage of research data can confer informational risk. This is the harm, including emotional harm and adverse effects on employment, that may result if private information about participants is released without consent.7Department of Health and Human ServicesHuman subjects research protections: enhancing protections for research subjects and reducing burden, delay, and ambiguity for investigators.Fed Regist. 2011; 76: 44512-44531Google Scholar Third, research activities differ with respect to opportunities for investigators and research participants to interact. Clinical trials that incorporate genomic testing into clinical care involve frequent face-to-face contact, providing an opportunity for participants to reaffirm or withdraw their agreement to participate. On the other hand, research activities that involve only analyses of previously banked DNA samples do not typically provide opportunities for investigators to interact with participants. Thus, the feasibility of renewing consent is affected by the nature of the research activities taking place when a research participant reaches the age of majority. The US regulations that prescribe how federally funded research with human subjects should be conducted, also known as the Common Rule, do not directly address the question of how consent should be handled when a participant reaches the age of majority. However, the Office of Human Research Protections (OHRP) provides direction on this issue in a set of Frequently Asked Questions. The responses to these questions about adolescent participants reaching the age of majority offer 3 regulatory alternatives.8Human Research Protections Frequently Asked Questions: What happens if a child reaches the legal age of consent while enrolled in a study?. U.S. Department of Health and Human Services, 2011http://answers.hhs.gov/ohrp/questions/7270Google Scholar First, research activities that involve "greater than minimal risk" cannot continue unless the research participant replaces the previous parental permission with his or her own informed consent. A research activity involves minimal risk when "the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests."9Definitions: Minimal Risk. 45 CFR 46.102(i) (2002).Google Scholar When a research activity that exceeds this standard continues after the participant reaches the age of majority, the authorization for participation must be updated. This is because the person legally empowered to authorize participation has changed, from the parent to the young adult participant. Second, IRBs have latitude to grant a waiver of consent to allow certain research activities to continue. Under the Common Rule, a waiver of consent can only be granted when the following 4 criteria are met: (1) the research involves no more than minimal risk to the subjects; (2) the waiver or alteration will not adversely affect the rights and welfare of the subjects; (3) the research could not practicably be carried out without the waiver or alteration; and (4) whenever appropriate, the subjects will be provided with additional pertinent information after participation.10General Requirements for Informed Consent. 45 CFR 46.116(d) (2002).Google Scholar These criteria explicitly mention factors that vary widely among genomic research activities, including both the risk conferred and the feasibility of contacting participants. Third, informed consent may not be required if the research falls outside the Common Rule's definition of "human subjects research." Specifically, the Common Rule defines a human subject as a person from whom an investigator obtains data through intervention or interaction, or from whom identifiable private information is obtained.11Definitions: Human Subject. 45 CFR 46.102(f) (2002).Google Scholar Building on this definition, the OHRP has clarified that research using de-identified biosamples and health information is not considered human subjects research whenever the following criteria are met: (1) the private information or specimens were not collected specifically for the currently proposed research project through an interaction or intervention with living individuals; and (2) the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain.12OHRPGuidance on Research Involving Coded Private Information or Biological Specimens. Office of Human Research Protections, Rockville, MD2004Google Scholar, 13OHRPGuidance on Research Involving Coded Private Information or Biological Specimens. Office of Human Research Protections, Rockville, MD2008Google Scholar In this regulatory context, such research on de-identified biosamples and health information is typically referred to as "nonhuman subjects research."14Brothers K.B. Clayton E.W. 'Human non-subjects research': privacy and compliance.Am J Bioeth. 2010; 10: 15-17Crossref PubMed Scopus (23) Google Scholar The ethical principle of respect for persons plays an important role in the Common Rule. The Belmont Report, the document that conceptually grounds the Common Rule, emphasizes a connection between respect for persons and recognition of autonomy. Respect for persons, the Report argues, "demands that subjects enter into the research voluntarily and with adequate information."15National Commission for the Protection of Human Subjects of Biomedical and Behavioral ResearchThe Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. National Institutes of Health, Bethesda, Maryland1979Google Scholar This principle, then, is the basis for the three regulatory alternatives provided by OHRP. Respect for persons can be interpreted more broadly, however. Many participants state that they expect the return of individual genomic results when they participate in a genomic study,16Fernandez C.V. Kodish E. Weijer C. Informing study participants of research results: an ethical imperative.IRB. 2003; 25: 12-19Crossref PubMed Scopus (198) Google Scholar and, thus, investigators reasonably consider the return of this information to be an expression of respect for persons. Investigators may also regard communication with participants through birthday cards, newsletters, and updates through social media as demonstrating respect for persons. Such efforts can help participants feel included in the research to which they have contributed and may provide participants with opportunities to learn more about research.17Anderson N. Bragg C. Hartzler A. Edwards K. Participant-centric initiatives: tools to facilitate engagement in research.Appl Transl Genom. 2012; 1: 25-29Crossref Scopus (25) Google Scholar In addition, these types of "engaged" approaches frequently serve the larger research enterprise by increasing participants' willingness to provide data, facilitating future research recruitment efforts, and improving relationships between the research institution and its community. Despite the recent popularity of "highly engaged" research, these approaches should not be construed as required by the principle of respect for persons. For many studies, the use of highly engaged approaches requires significant tradeoffs. The maintenance of long-term relationships and the return of research results require significant investments of time and money. When investigators are not funded for these activities, or when important scientific aims can best be attained using less engaged approaches, respect for persons can be demonstrated in other ways. Investigators and institutions should, for example, exercise responsible stewardship of biosamples and carefully protect research data.18Schwarzkopf G.M. Bartram C.R. Eils R. von Kalle C. Kirchhof P. Korbel J. et al.Cornerstones for an ethically and legally informed practice of whole genome sequencing: Code of conduct and patient consent models. Marsilius-Kolleg, Heidelberg2013Google Scholar Breaking a research study into its component activities can facilitate a decision about which of the 3 regulatory alternatives proposed by the OHRP is appropriate in a given situation. Investigators who conduct interventional research activities interact directly with research participants. Genomic interventional research activities include those that provide participants with genomic research results and studies in which genomic information is used to modify clinical care. A pharmacogenomics study comparing the effectiveness of genome-guided prescribing with conventional practice exemplifies the latter. Interventional research activities should continue into adulthood only if the participant provides his or her explicit consent. This is usually feasible because interventional research activities typically provide ample opportunities for investigators and participants to interact. Because of this, they rarely meet the criterion that the research could not practicably be carried out without a waiver of consent. Many noninterventional research activities do not involve direct interaction between investigators and participants. In genomic research, the most common noninterventional activity is the analysis of banked biosamples and data. The most appropriate consent model for this type of research activity depends on 2 related factors: the type of information retained and the level of engagement that investigators maintain with participants. If no identified data are stored, there can be no engagement between investigators and participants. This is frequently the case in certain types of biorepositories where the precise timing of a participant's transition to adulthood is not known because the birthdate, an identifier under the Health Insurance Portability and Accountability Act, is not retained.19Roden D.M. Pulley J.M. Basford M.A. Bernard G.R. Clayton E.W. Balser J.R. et al.Development of a large-scale de-identified DNA biobank to enable personalized medicine.Clin Pharmacol Ther. 2008; 84: 362-369Crossref PubMed Scopus (625) Google Scholar In this type of study, analyses typically continue regardless of whether a participant has reached the age of majority.20Brothers K.B. Biobanking in pediatrics: the human nonsubjects approach.Per Med. 2011; 8: 71-79Crossref Scopus (29) Google Scholar More commonly, pediatric data and samples are collected in a larger research study in which identifiers are retained. For this type of research activity, investigators must decide: (1) whether they will attempt to contact participants to obtain their consent; and (2) whether it is appropriate to continue analyzing samples from participants whose consent is not obtained. In order to continue using identified samples without the young adult's consent, the IRB must grant a waiver of consent. For this reason, these decisions hinge on the criteria for a waiver of consent set out in the Common Rule. Of the 4 criteria, practicability is usually decisive because noninterventional research activities usually confer only minimal risk, and a waiver of consent in this context does not typically limit the rights and welfare of subjects. Practicability can be difficult to operationalize. The Common Rule does not define practicability, and there is no guidance from OHRP that addresses its meaning. However, the Secretary's Advisory Committee on Human Research Protections (SACHRP) has offered several useful observations about practicability in a nonbinding letter.21Tilden S. SACHRP Letter to HHS Secretary (Topic: Waiver of Consent). In: Secretary's Advisory Committee on Human Research Protections, ed. Washington, D.C., 2008. http://www.hhs.gov/ohrp/sachrp/20080131secretarialadvisoryletter.pdf.Google Scholar SACHRP emphasized that the requirement to obtain consent should only be waived when such a requirement would preclude researchers from attaining a study's research objectives as a result of biasing results, significantly decreasing statistical power, or preventing meaningful conclusions from being drawn.21Tilden S. SACHRP Letter to HHS Secretary (Topic: Waiver of Consent). In: Secretary's Advisory Committee on Human Research Protections, ed. Washington, D.C., 2008. http://www.hhs.gov/ohrp/sachrp/20080131secretarialadvisoryletter.pdf.Google Scholar Although SACHRP warns against judging practicability on the basis of convenience, cost, or speed alone, it makes it clear in its letter that these factors do matter if they would prevent scientifically valid research from taking place. SACHRP's letter addresses waiver of consent at the onset of research but does not directly address the issue of contacting previous pediatric research participants to obtain their consent at the age of majority. In addition, the letter assumes that decisions about a waiver would apply to all participants in a study. In contrast, noninterventional genomic research activities often involve a mix of previously enrolled participants: some might be reached for their consent, while others might not be reachable. We believe, however, that the general principles proposed by SACHRP can be interpreted in the following way: (1) whenever possible, consent should be sought and obtained; (2) it is only appropriate to forego contacting participants for their consent when this effort would preclude investigators from attaining important research aims; and (3) in cases where a participant cannot be reached successfully, or when the IRB deems the requirement to contact participants impracticable, investigators may continue using data and samples from participants under a waiver of consent. This interpretation of the regulation in light of SACHRP's analysis has several important implications. First, most noninterventional research activities involving identified data will require investigators to reach out to participants as they reach the age of consent. In these cases, investigators should work prospectively with their local IRB to develop a contact plan that is practicable in the context of the study's research aims and resources, and which specifies when an effort to contact a participant could be deemed unsuccessful. In rare circumstances, however, the local IRB could determine that an effort to contact participants would be impracticable in the context of a particular study, meaning that such effort would prevent the investigators from attaining important research aims. This might apply, for example, to a study with very large numbers of participants or participants who were lost to follow-up many years prior. In this case, the IRB might issue a waiver of consent to allow research to continue without an effort to contact participants. A second implication of this analysis is that it may be appropriate to retain identifiable samples and data after participants reach the age of majority, even if they cannot be reached for their consent. This conclusion runs counter to practices at some institutions, where IRBs may require samples and data to be de-identified when participants reaching the age of majority cannot be contacted for their consent.22Brothers K.B. Lynch J.A. Aufox S.A. Connolly J.J. Gelb B.D. Holm I.A. et al.Practical guidance on informed consent for pediatric participants in a biorepository.Mayo Clin Proc. 2014; 89: 1471-1480Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Some IRBs even require investigators to destroy samples and data in this circumstance.22Brothers K.B. Lynch J.A. Aufox S.A. Connolly J.J. Gelb B.D. Holm I.A. et al.Practical guidance on informed consent for pediatric participants in a biorepository.Mayo Clin Proc. 2014; 89: 1471-1480Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Notably, even though many sites adopt these practices, there is no strong evidence that participants prefer to have their data and samples de-identified or destroyed if they cannot be contacted. In one study, 54% of adult respondents believed researchers should not have to ask for consent to continue using banked samples once adolescents reach adulthood. Of the respondents who believed researchers should attempt to locate participants to obtain their consent, 41% found it acceptable for researchers to continue using the samples of participants who could not be located.23Goldenberg A.J. Hull S.C. Botkin J.R. Wilfond B.S. Pediatric biobanks: approaching informed consent for continuing research after children grow up.J Pediatr. 2009; 155: 578-583Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Patients affected with serious and chronic illnesses in particular are often enthusiastic about the use of their data and samples to improve care for future patients.24Brothers K.B. Clayton E.W. Parental perspectives on a pediatric human non-subjects biobank.Am J Bioeth. 2012; 3: 21-29Google Scholar, 25Helft P.R. Champion V.L. Eckles R. Johnson C.S. Meslin E.M. Cancer patients' attitudes toward future research uses of stored human biological materials.J Empir Res Hum Res Ethics. 2007; 2: 15-22Crossref PubMed Google Scholar, 26Tabor H.K. Stock J. Brazg T. McMillin M.J. Dent K.M. Yu J.H. et al.Informed consent for whole genome sequencing: a qualitative analysis of participant expectations and perceptions of risks, benefits, and harms.Am J Med Genet A. 2012; 158A: 1310-1319Crossref PubMed Scopus (98) Google Scholar, 27Bui E.T. Anderson N.K. Kassem L. McMahon F.J. Do participants in genome sequencing studies of psychiatric disorders wish to be informed of their results? A survey study.PLoS One. 2014; 9: e101111Crossref PubMed Scopus (25) Google Scholar And as we will discuss in the next section, many research participants wish to receive important research results.28McGowan M.L. Glinka A. Highland J. Asaad G. Sharp R.R. Genetics patients' perspectives on clinical genomic testing.Per Med. 2013; 10: 339-347Crossref PubMed Scopus (30) Google Scholar, 29Facio F.M. Eidem H. Fisher T. Brooks S. Linn A. Kaphingst K.A. et al.Intentions to receive individual results from whole-genome sequencing among participants in the ClinSeq study.Eur J Hum Genet. 2013; 21: 261-265Crossref PubMed Scopus (138) Google Scholar, 30Sapp J.C. Dong D. Stark C. Ivey L.E. Hooker G. Biesecker L.G. et al.Parental attitudes, values, and beliefs toward the return of results from exome sequencing in children.Clin Genet. 2014; 85: 120-126Crossref PubMed Scopus (105) Google Scholar Both de-identification and destruction of samples and data preclude returning these results in the future. Investigators may also have important reasons for wanting to retain a link to identifying data. They may hope that contact can be reestablished in the future so that research results can be returned to participants, so they can obtain follow-up data, or so they can follow-up with participants to answer research questions that were not anticipated when the original study was conceived.31Seeff L.B. Miller R.N. Rabkin C.S. Buskell-Bales Z. Straley-Eason K.D. Smoak B.L. et al.45-year follow-up of hepatitis C virus infection in healthy young adults.Ann Intern Med. 2000; 132: 105-111Crossref PubMed Scopus (326) Google Scholar Their research aims might also require the analysis of characteristics that are inherently identifying, such as dates or geolocations. Taking these factors into account, we believe local IRBs should encourage researchers to prospectively develop and implement plans for contacting adolescents to obtain their consent when they reach adulthood. When attempts to contact are not successful, however, IRBs should be willing to use the waiver of consent mechanism to allow identified data and samples to be retained. Although this approach would allow research without explicit consent from young adult participants, it can still be done in a way that demonstrates respect for persons. For example, whenever possible an honest broker approach should be used to reduce informational risk. In this approach, investigators performing analyses work with coded data, and the key that links the coded data back to participant identifiers is retained by an honest broker.32Boyd A.D. Hosner C. Hunscher D.A. Athey B.D. Clauw D.J. Green L.A. An 'Honest Broker' mechanism to maintain privacy for patient care and academic medical research.Int J Med Inform. 2007; 76: 407-411Crossref PubMed Scopus (50) Google Scholar, 33Yassin R. Lockhart N. González del Riego M. Pitt K. Thomas J.W. Weiss L. et al.Custodianship as an ethical framework for biospecimen-based research.Cancer Epidemiol Biomarkers Prev. 2010; 19: 1012-1015Crossref PubMed Scopus (47) Google Scholar The honest broker can re-identify records if needed to reestablish contact, such as when a compelling individual research result is uncovered that the investigator wants to return to the subject. In the preceding sections, we argued that current regulations require different approaches to consent at the age of majority for interventional and noninterventional research activities. Interventional research activities nearly always require explicit consent, and noninterventional studies may qualify for a waiver of consent or a nonhuman subjects approach. Research activities that potentially involve the disclosure of individual research results represent a special case, however, because this practice has the potential to fall into more than 1 category. Specifically, disclosing research results can be an interventional research activity if this is a planned part of the study. This is especially true if the intention is to gather data about how this information influences outcomes such as healthcare utilization, adoption of preventive measures, or psychological responses. In this case, the approach to consent when a participant reaches the age of majority is straightforward. Like other types of interventional genomic research, this research activity typically requires informed consent because the ongoing interaction increases the feasibility of obtaining consent when participants reach the age of majority. In contrast, some investigators only intend to disclose research results to participants in whom a clinically significant research result has been discovered.34Ramoni R.B. McGuire A.L. Robinson J.O. Morley D.S. Plon S.E. Joffe S. Experiences and attitudes of genome investigators regarding return of individual genetic test results.Genet Med. 2013; 15: 882-887Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 35Klitzman R. Appelbaum P.S. Fyer A. Martinez J. Buquez B. Wynn J. et al.Researchers' views on return of incidental genomic research results: qualitative and quantitative findings.Genet Med. 2013; 15: 888-895Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar This type of research activity differs from studies that involve disclosure of results to all participants, because there is only a possibility, not a certainty, that any particular participant will receive a result. Also, such results will be selected for disclosure on the basis of their potential to provide benefit to the participant, not to answer research questions. For these reasons, the requirements for consent differ. Consent should still be sought whenever practicable. However, when a participant cannot be reached for consent, in most cases it is reasonable to continue analysis on his or her identified sample (or to use an honest broker to retain identifiers) with the intention of attempting contact again if an important genomic result is discovered. When such an approach is used, a high threshold designed to minimize risks to participants should be used in deciding whether to contact a participant to disclose a result. IRBs should also ensure that the process for returning results protects the rights and interests of participants. Returning to the 3 case vignettes introduced earlier, we can see that investigators and the IRB can anticipate these challenges at the start of the study. When such a study is proposed, investigators and the IRB should prospectively agree on a plan that describes when and how, or whether, investigators will attempt to contact participants reaching the age of majority. The plan should also describe how samples and data will be handled when participants cannot be successfully reached. As we have argued here, there is a range of options compliant with current regulations, including several that would permit important research to continue even if participants cannot be reached.

In the decade since the Human Genome Project was completed, the knowledge and technologies that this project enabled have led to a remarkable evolution in the way biorepositories are designed and operated. Early biobanks were often designed to facilitate the study of a single condition, whereas biobanks established in the past decade have more frequently been created with a broader research mission in mind.1Henderson G.E. Cadigan R.J. Edwards T.P. et al.Characterizing biobank organizations in the U.S.: results from a national survey.Genome Med. 2013; 5: 3Crossref PubMed Scopus (157) Google Scholar Accompanying this transition have come other changes in biobank practices, including the generation and storage of genome-scale sequencing data, frequent sharing of biosamples and data, pooling of resources among sample collections, and increased interest in returning genetic research results to sample donors. As biorepository practices have become more complex, the task of developing appropriate informed consent practices has become more challenging. There are at least 3 reasons for this. First, the regulations that govern research with human subjects in the United States, known collectively as the Common Rule, were written at a time when many of the recent innovations in biobank practices were not anticipated. Second, institutional review boards (IRBs) are tasked with evaluating whether research studies meet federal regulations and local standards for acceptable research, yet IRB members are often unfamiliar with the complexities of biobanks. Third, it can be challenging to explain these practices in informed consent documents in a way that is easy for potential research participants to read and understand. Because of these challenges, several groups have developed practical guidance on informed consent. For example, the website of the National Human Genome Research Institute (NHGRI), Genome.gov, provides model informed consent language developed for genomic research studies, including biobanks.2Informed consent elements tailored to genomics research. National Human Genome Research Institute website. http://www.genome.gov/27026589. Accessed July 2, 2013.Google Scholar The NHGRI website also hosts a white paper developed by our group, the Electronic Medical Records and Genomics (eMERGE) Network.3Beskow L.M. Clayton E.W. Eisenberg L. et al.Model Consent Language. The Electronic Medical Records and Genomics (eMERGE) Network Consent & Community Consultation Workgroup Informed Consent Task Force, 2009: 1-14http://www.genome.gov/Pages/PolicyEthics/InformedConsent/eMERGEModelLanguage2009-12-15.pdfGoogle Scholar This document provides model language for informed consent documents that investigators may adapt for their own biorepository projects. One limitation of these resources, however, is their focus on adult research participants. There are currently no similar resources that address the unique issues that arise for biorepositories that aim to collect samples from pediatric participants. This is an important gap in the literature because the challenges associated with biobanking are magnified in the setting of pediatric research. The ability of children to engage in informed decision making varies according to their developmental level, so parental permission is usually required for pediatric research participation. However, a parent's permission for a child to participate in research is quite different from an adult's consent for his or her own research participation. A parent's decision must account for the best interests of the child while balancing the future autonomy of the child and the needs of the family. To be sure, there is a robust literature on these unique issues that arise in pediatric research,4Ross L.F. Informed consent in pediatric research.Camb Q Healthc Ethics. 2004; 13: 346-358Crossref PubMed Google Scholar, 5Wendler D.S. Assent in paediatric research: theoretical and practical considerations.J Med Ethics. 2006; 32: 229-234Crossref PubMed Scopus (96) Google Scholar including a variety of helpful papers that address pediatric biorepositories specifically.6Hens K. Nys H. Cassiman J.J. Dierickx K. Biological sample collections from minors for genetic research: a systematic review of guidelines and position papers.Eur J Hum Genet. 2009; 17: 979-990Crossref PubMed Scopus (38) Google Scholar, 7Hens K. Van El C.E. Borry P. et al.Developing a policy for paediatric biobanks: principles for good practice.Eur J Hum Genet. 2013; 21: 2-7Crossref PubMed Scopus (55) Google Scholar However, it can be difficult for investigators and IRB members to distill these empirical and analytical resources into concrete practices related to the informed consent process. This document is designed to address that need. Writing on behalf of the Consent, Education, Regulation, and Consultation Workgroup of the eMERGE Network, we provide pediatric-focused guidance for investigators and IRB members working in the US regulatory context on pediatric informed consent practices for biorepositories. Investigators from 8 eMERGE Network sites, including 7 sites with direct experience obtaining informed consent for the inclusion of pediatric samples in biorepositories, collaborated on this project. The eMERGE Network comprises sites that have developed prospective biobanks that are linked with data derived from electronic health records. To collect the experience of these sites, investigators sent one of us (K.B.B.) IRB-approved informed consent and assent documents that were in active use for eMERGE Network–affiliated biorepositories during 2012, along with any ancillary protocols or documentation related to pediatric consent. In all, investigators submitted documents related to 9 projects (1 institution submitted documents relating to 3 independent biobanking projects). The research team then conducted a qualitative, thematic analysis of the documents. Themes were developed through an iterative process that involved review of conceptual literature on pediatric issues in biobanking, discussion of site-specific experiences, and review and close reading of the available consent and assent documents. The full author team reached consensus on 7 themes relevant to pediatric biobanking: permission from parents, assent from minors, co-consent from older adolescents, data sharing, return of results, recontacting participants, and retention of samples after the age of majority. Codes were then developed for each theme through an iterative process that involved individual review of consent and assent documents, collation of proposed codes, and group discussion to reach consensus. Codes fell into 2 general categories. First, codes were developed to record whether each thematic issue was addressed in a given consent or assent document. For example, 1 code was developed to tag consent documents that explicitly mentioned data sharing. A parallel set of codes recorded how those thematic issues were operationalized in the language of consent and assent documents. For example, the language mentioning data sharing was categorized using a set of codes specifying which recipients of shared data were explicitly mentioned. These codes were structured into a REDCap database that was used to summarize the characteristics of each consent and assent document. One of us (K.B.B.) performed the initial coding for all the documents, and at least 1 investigator from each site reviewed these codes for accuracy. All disagreements were resolved by consensus between one of us (K.B.B.) and local site representatives, followed by a final review and consensus approval of the aggregate coding by the entire research team. The research team then used investigator triangulation to analyze the results of the coding.8Denzin N.K. The Research Act in Sociology: A Theoretical Introduction to Sociological Methods. Butterworths, London, England1970Google Scholar Specifically, team members reviewed the aggregate results of the coding to identify potential conclusions about the results that could provide guidance for the development of future consent and assent documents. These initial conclusions were then refined through a process involving discussion on specific site experiences, review of available literature on related ethics or compliance issues, and analysis of relevant ethical or regulatory concepts. This triangulation process occurred over several conference calls and led to a final consensus on guidance for each of the ethical and regulatory issues reflected in the thematic coding. Two overarching themes emerged as important to nearly every issue we examined: the evolving roles of parents and children in making decisions related to research participation as children mature and the role of the IRB. In broad terms, the Common Rule requires that the permission to enroll a minor in a research study must come from his or her parent or guardian. From a compliance perspective, minors cannot give consent until they reach the age of majority, which is usually 18 years of age. At the same time, it is clear that children do not suddenly become fully mature adults at this age. The ability of children to participate in decisions, including those related to research participation, develops over a period, with significant variation in its timing from child to child. From an ethics perspective, then, it is favorable to engage each child in the informed consent process in a way that is responsive to his or her current state of development. Legal authorization to participate still must come from a parent or guardian, but the duty to inform a child and to respect his or her concerns and preferences must be respected in proportion to his or her developing autonomy. The Common Rule requires that a child assent to research participation unless it can be appropriately waived or the child is not capable of providing it. This tension between the legal status of a minor and the duty to respect his or her developing ability to engage in an assent process is a key issue that informs every piece of guidance addressed in this document. The second overarching theme that emerged in our work was the important role IRBs play in decisions about the participation of children in biobanks. The guidance provided in this document is informed by our own experiences as investigators working with local IRBs to develop assent, consent, and parental permission procedures for biorepositories at each of the 8 participating eMERGE Network institutions. Although our experiences with our local IRBs varied significantly, we were able to identify a variety of commonalities. For example, IRBs at the eMERGE Network sites often provided investigators with guidelines on pediatric-specific research issues, including specific cutoff ages for asking children to provide assent. Local IRBs also often required that certain blocks of language be included in every consent document. Some eMERGE Network investigators found these guidelines frustrating because local IRB guidelines may differ from standards adopted elsewhere. More important, some investigators may desire to adopt practices that are more nuanced or more individualized than those recommended by the IRB. This document is designed, in part, to address these challenges. In our experience, IRB professionals and committee members are often responsive to respectful discussions about best practices related to informed consent, assent, and parental permission. We believe that these discussions can be facilitated by practical guidance that reflects the practices of other institutions and the most up-to-date thinking about research ethics and compliance issues. Although we anticipate that institutions will continue to find good reasons for doing things differently from the approach we propose herein, we hope that this document will serve as a starting point for thoughtful local discussions on how best to protect children while developing biorepositories that could provide significant scientific utility. In the sections that follow, we present guidance on a variety of pediatric-specific consent issues that arise frequently in the development of biorepositories. Because biorepository designs and local conditions vary, we endeavored to provide broad guidance that is applicable in as many contexts as possible. Each piece of guidance is accompanied by a summary of the experiences of the eMERGE Network sites, followed by a discussion of key issues. Permission from 1 parent is adequate for a child's participation in a biorepository. All 9 eMERGE Network projects examined by our group required the permission of only 1 parent. The Common Rule requires consent from both parents when the research planned is not expected to provide direct benefit to participating children but confers a greater-than-minimal risk to them.9US Department of Health and Human Services. Additional Protections for Children Involved as Subjects in Research: 45 CFR 46.406 and 46.407. 2009. Washington, DC: US Dept of Health and Human Services.Google Scholar Such studies are not generally allowed unless they are (1) likely to yield generalizable knowledge about the individual participant's condition or (2) present an opportunity to "understand, prevent, or alleviate a serious problem affecting the health or welfare of children."9US Department of Health and Human Services. Additional Protections for Children Involved as Subjects in Research: 45 CFR 46.406 and 46.407. 2009. Washington, DC: US Dept of Health and Human Services.Google Scholar Studies of both types require the permission of both parents unless the child has just 1 parent or legal guardian. The primary risk faced by biorepository participants is the disclosure of their private information to others. This risk is generally classified as minimal because it is similar to that encountered in routine clinical care. The return of genomic results may create additional risks for participants, but results should usually be returned only if they also carry the potential to provide direct benefit for participants. Given these features of biorepositories, the Common Rule allows the enrollment of pediatric participants with permission from just 1 parent. An ethical analysis supports this conclusion because a requirement for permission from both parents is likely to hinder enrollment while providing no substantive improvement in the quality of the informed consent.4Ross L.F. Informed consent in pediatric research.Camb Q Healthc Ethics. 2004; 13: 346-358Crossref PubMed Google Scholar Developmentally appropriate explanations about biorepository participation are recommended for all children. The projects analyzed by our working group depend primarily on the verbal explanations of study personnel adapted to the child's developmental level, with all 9 projects using this approach. Seven projects also use assent documents that provide brief written information. None of the eMERGE Network projects examined use additional written materials, such as pamphlets or multimedia tools, to explain research procedures to children. Even children who are not being asked to provide assent deserve a developmentally appropriate explanation about the research process. The amount of information given and the level of detail used to describe participation in a biobank should be based primarily on a child's developmental level,10Wilfond B.S. Diekema D.S. Engaging children in genomics research: decoding the meaning of assent in research.Genet Med. 2012; 14: 437-443Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar as assessed by the study personnel conducting the assent process. This assessment can be based on input from the child's parent or guardian and on preliminary conversations with the child. Children at earlier stages of development should, at minimum, receive an explanation about study procedures, such as the blood collection or buccal swab. More mature children should receive a brief description of the aims of the biobank. Adolescents whose developmental level approaches that of young adults should receive essentially the same information as their parents. These explanations can be provided in a range of formats, including verbal explanations, demonstrations by certified child life experts, and written descriptions. When used, assent documents should be written at an appropriate readability level, but even then such language is only a starting point. Additional resources, such as videos, comic books, and interactive websites, may help provide developmentally appropriate descriptions for children and adolescents enrolling in a biorepository. Because evidence on the effectiveness of these tools is currently incomplete, this is an area ripe for examination and empirical study in the setting of pediatric biobanks. We believe that, for the present, multimedia tools should be used primarily to facilitate interpersonal engagement and not to replace it. In addition to developmentally appropriate explanations, some children should also be asked to provide assent. Requests for assent are appropriate once participants reach the developmental level similar to that of a typically developing 7- to 10-year-old or when parents report that the child is mature enough to understand and participate in this process. All 9 eMERGE Network projects use assent in some form, with most using local guidelines based on age rather than developmental level. The starting age for requesting assent ranges from 7 to 12 years. Two projects require written assent, and 2 require only verbal assent. Five allow the use of either written or verbal assent, depending on the circumstances (ie, the child's developmental level). Written assent documents range from approximately 200 to 1200 words. Local IRBs often set guidelines for the use of verbal or written assent and usually specify an age range for assent. However, we recommend going beyond chronological age. Study personnel obtaining assent should consider each child's developmental stage and cognitive ability to ensure that both explanations and the use of assent procedures are appropriate.11Joffe S. Fernandez C.V. Pentz R.D. et al.Involving children with cancer in decision-making about research participation.J Pediatr. 2006; 149: 862-868.e861Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar These personnel should be trained to make a decision about when assent should be elicited based on observations of or conversations with the child and the input of the parent or guardian, and to document their decision and rationale. In general, either written or verbal assent could be appropriate for biobank participation depending on the child's developmental level. Whenever a child's assent is needed for enrollment, his or her dissent should be respected. These issues are not substantially different from other types of research, so general resources on research assent and dissent can be helpful in this setting.4Ross L.F. Informed consent in pediatric research.Camb Q Healthc Ethics. 2004; 13: 346-358Crossref PubMed Google Scholar, 12AAP Committee on BioethicsInformed consent, parental permission, and assent in pediatric practice.Pediatrics. 1995; 95: 314-317PubMed Google Scholar It may be advisable to engage more mature adolescents in a co-consent process rather than an assent process. This approach would be appropriate for adolescents who have reached a developmental level comparable with that of a typical 14-year-old. One project analyzed in this study provides a signature line on the consent document for older adolescents who are being asked to provide co-consent. Permission from a parent is also required. Adolescents in their late teen years are often mature enough to engage in consent-like conversations and to consider the risks and benefits of participation in the same way an adult would. Although these young people are not legally authorized in most circumstances to provide consent for their research participation, from an ethical perspective it is appropriate to focus the informed consent process as much on the adolescents' deliberative process as on that of their parents. This approach has several advantages. First, it reflects respect for the adolescent's emerging autonomy.13Broome M.E. Kodish E. Geller G. Siminoff L.A. Children in research: new perspectives and practices for informed consent.IRB. 2003; Suppl 25: S20-S23Crossref PubMed Scopus (27) Google Scholar Second, the preferences expressed by mature adolescents may provide guidance about how to manage their samples should investigators not be able to recontact them when they reach the age of majority. We discuss this second issue below. The sharing of deidentified data is inherent in the scientific aims of biorepositories and is considered appropriate for pediatric biobanks. Potential participants should be provided with a general explanation of any plans to share samples or data, including the associated risks and benefits. The data-sharing experiences of the eMERGE Network sites has been described in detail in a previous publication.14McGuire A.L. Basford M. Dressler L.G. et al.Ethical and practical challenges of sharing data from genome-wide association studies: the eMERGE Consortium experience.Genome Res. 2011; 21: 1001-1007Crossref PubMed Scopus (64) Google Scholar Pediatric-specific consent documents from all 9 eMERGE Network projects mention data sharing. Four of these projects mention that data could be shared with national databases, such as the Database of Genotypes and Phenotypes (dbGaP0), and with other research institutions (an example is provided in Figure 1). The consent documents from 2 projects mention only national databases as potential recipients of data, and 1 project's consent document mentions only other research institutions as potential recipients. The consent documents for 2 projects ask parents to choose whether they wish for their child's data to be shared. The distinctions among identifying data, deidentified data, and anonymous data are key to the issue of data sharing. In the United States, most institutional biobanks retain data with identifiers but share only deidentified data. This is because the Privacy Rule portion of the Health Information Portability and Accountability Act restricts the distribution of identifying health information. The Privacy Rule does allow deidentified data to be shared and specifies the criteria that must be met for data to be considered deidentified for these purposes.15US Department of Health and Human Services. Other Requirements Relating to Uses and Disclosures of Protected Health Information: 45 CFR 164.514. 2011. Washington, DC: US Dept of Health and Human Services.Google Scholar Some research data, such as genetic markers, are clearly not anonymous even if they are deidentified according to the Privacy Rule. Once deidentified data are shared outside the original institution, it is not usually possible to retract it, even if the parent, or later the young adult who had participated in research as a child, wishes to withdraw from the biobank. One group of commentators has argued that for this reason, and because shared genetic data are not anonymous, data collected from children for population-based biobanks should not be shared until the child reaches adulthood and consents to data sharing.16Gurwitz D. Fortier I. Lunshof J.E. Knoppers B.M. Research ethics: children and population biobanks.Science. 2009; 325: 818-819Crossref PubMed Scopus (72) Google Scholar Although we agree that the genetic information of minors deserves careful protection, we do not agree that this protection needs to involve a delay in sharing data. There are numerous other ways to protect the confidentiality of pediatric participants, including through the use of data-use agreements and proper security measures.17Brothers K.B. Clayton E.W. Biobanks: too long to wait for consent.Science. 2009; 326: 798Crossref PubMed Scopus (18) Google Scholar In addition, such constraints undermine the future health benefits for children that motivate the creation of biobanks. Each pediatric biorepository should develop a policy for how data and samples will be handled once a pediatric participant reaches the age of majority, and should explain this policy in its consent document. The policies of all 9 eMERGE Network projects allow for data and samples to be retained once participants reach the age of majority. One project deidentifies all samples and data, making recontact potentially unnecessary. The remaining 8 projects attempt to recontact participants when they reach the age of majority. These projects differ in their policies regarding participants who cannot be reached. Six projects plan to deidentify data from such participants, and 1 site plans to destroy their data. One project permits older adolescents to choose whether they want their samples to be deidentified or destroyed if they cannot be reached (Figure 2). Eight of the 9 projects explain their retention policies in their consent documents. Generally speaking, there are at least 2 decisions that biobanks need to make when it comes to developing a policy for the management of data and samples from participants who have reached the age of majority. They must first decide whether the biorepository will attempt to recontact young adults to obtain their consent to continued use of data and samples. Recontact is preferable in many circumstances because this approach affirms the importance of first-person consent. However, this principle must be balanced with the feasibility and cost of such an effort. For example, recontact would probably not be required, either from an ethical or a compliance perspective, in cases in which a biorepository had so many participants that recontacting them would be unfeasible. Because it is inevitable with either policy that at least some participants will not be reached, biobanks must also decide how to handle data and samples from participants who are not recontacted. In our sample, the most common policy is to deidentify data and samples from participants who are not recontacted. We believe that this approach is relatively uncontroversial, especially because the Office of Human Research Protections has released a guidance document clarifying that research with deidentified data and samples is considered non–human subjects research and does not require informed consent.18Office of Human Research ProtectionsGuidance on Research Involving Coded Private Information or Biological Specimens. Office of Human Research Protections, Rockville, MD2008Google Scholar This approach is also likely to be acceptable to most biobank participants.19Goldenberg A.J. Hull S.C. Botkin J.R. Wilfond B.S. Pediatric biobanks: approaching informed consent for continuing research after children grow up.J Pediatr. 2009; 155: 578-583Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar There are other options, however. In certain circumstances, identified data may be used for research even if the participant cannot be contacted. Although the use of identified data for research generally requires explicit informed consent, the Common Rule allows IRBs to waive this requirement in specific circumstances, such as when "the research could not practicably be carried out without the waiver."20US Department of Health and Human Services. General Requirements for Informed Consent: 45 CFR 46.116(d). 2009. Washington, DC: US Dept of Health and Human Services.Google Scholar To meet this criterion, biobanks would need to demonstrate to the IRB that the scientific aims of the biobank can be achieved only if data and samples remain associated with identifiers. A final option is to destroy the biosamples and research data collected from participants who cannot be reached when they reach the age of majority. This approach was required by the IRB at one of our sites. We do not recommend this approach, however, because it is likely to compromise the scientific aims of any pediatric biobank that is unable to recontact a large proportion of its participants, and also because other privacy protections are available. As we observed earlier, less restrictive approaches to protecting participants' privacy are well received by most biobank participants.19Goldenberg A.J. Hull S.C. Botkin J.R. Wilfond B.S. Pediatric biobanks: approaching informed consent for continuing research after children grow up.J Pediatr. 2009; 155: 578-583Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Given the wide range of biorepository designs, scientific aims, and institutional capacities, and in light of the current lack of professional consensus about whether and how to return genetic research results, it is acceptable for a biorepository to return results or to not return results to pediatric participants and their parents. Of the 9 projects included in the analysis, 2 do not mention return of results in the consent document, 2 state that results will not be returned to participants, and 5 state that research results might be returned to participants. The assent document for only 1 project mentions the return of research results; this document is from one of the sites that does not plan to return results. The relevant language from each of these consent documents, and 1 assent document, is listed in the Supplemental Table (available online at http://www.mayoclinicproceedings.org). Among the 5 projects returning results, the details provided in the consent document vary widely. Three projects provide relatively brief information focused on informing participants that they may be contacted if a useful genetic result is identified. Two projects provide more detailed information, including information on how returnable results will be identified and how results will be communicated to participants. None of the projects we reviewed include the explicit criteria that will be used for evaluating whether a result should be returned. The 2 projects that provide detailed information instead focus on the procedure that will be used to review results and identify which will be returned, including a description of the committee that will make such decisions. Biorepositories raise a distinctive set of challenges for returning genetic research results to participants. For example, research performed using biorepository data is often conducted by investigators far removed from the participants themselves. For this reason, it can be difficult for investigators to evaluate whether a participant would want to know a result. Similarly, research with children raises its own distinctive set of challenges for returning research results. Consider, for example, that a current policy statement from the American Academy of Pediatrics and the American College of Medical Genetics and Genomics (ACMG) advises against testing children for certain adult-onset genetic conditions, a policy relevant to deciding which genetic research results should be considered for return to a pediatric research participant.21AAP Committee on Bioethics, AAP Committee on Genetics, ACMG Social Ethical and Legal Issues CommitteeEthical and policy issues in genetic testing and screening of children.Pediatrics. 2013; 131: 620-622Crossref Scopus (254) Google Scholar, 22Ross L.F. Saal H.M. David K.L. Anderson R.R. Technical report: ethical and policy issues in genetic testing and screening of children.Genet Med. 2013; 15: 234-245Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar, 23Clayton E.W. Addressing the ethical challenges in genetic testing and sequencing of children.Am J Bioeth. 2013; 14: 3-9Crossref Scopus (83) Google Scholar In contrast, a policy statement from a different committee of the ACMG proposes that potential benefit to parents is a compelling reason to return incidental findings for certain adult-onset conditions.23Clayton E.W. Addressing the ethical challenges in genetic testing and sequencing of children.Am J Bioeth. 2013; 14: 3-9Crossref Scopus (83) Google Scholar, 24Green R.C. Berg J.S. Grody W.W. et al.ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Genet Med. 2013; 15: 565-574Abstract Full Text Full Text PDF PubMed Scopus (1834) Google Scholar It is clear, then, that the already complex issue of whether and when to return research results is made even more complex in the setting of pediatric biobanking. The current iteration of the eMERGE Network was designed, in part, to explore how research results generated through biorepositories could be returned to participants and their medical providers. Institutions both interested in and equipped to address the relevant challenges are overrepresented in our group. We recognize, however, that not all institutions pursuing the development of a biorepository will be interested in, or capable of, returning research results. In fact, it is possible that at some institutions the development of an otherwise valuable biorepository could be significantly impeded if an infrastructure for returning research results were required. Given this set of considerations, we consider it acceptable for pediatric biobanks to be designed to return results or to not return results, although we acknowledge that there is no consensus on this matter.25Bledsoe M.J. Grizzle W.E. Clark B.J. Zeps N. Practical implementation issues and challenges for biobanks in the return of individual research results.Genet Med. 2012; 14: 478-483Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 26Presidential Commission for the Study of Bioethical Issues. Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts. Washington, DC; 2013.Google Scholar, 27Clayton E.W. McGuire A.L. The legal risks of returning results of genomics research.Genet Med. 2012; 14: 473-477Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 28Wolf S.M. Crock B.N. Van Ness B. et al.Managing incidental findings and research results in genomic research involving biobanks and archived data sets.Genet Med. 2012; 14: 361-384Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar Institutions considering the development of a biobank that will include samples from children should carefully consider the potential benefits and opportunity costs associated with returning results and should develop a policy that is acceptable to local stakeholders. Whatever the policy developed, it is important that parents being asked to consent to their child's participation be provided with a clear and understandable explanation of these plans. Biobanks choosing to return results should take individual participant preferences into account. These preferences may be elicited at the time of informed consent or during a later interaction. When an adolescent is mature enough to weigh the relevant risks and benefits, most results should be returned only when both the adolescent and his or her parents agree that they want to receive it. Of the 5 consent documents that state that results could be returned, 2 ask parents to record a preference about receiving research results. In both cases, the consent document asks the parent only to accept or decline potential return of results, but both mention later opportunities to accept or decline specific results. None of the assent or consent documents directly elicit the preferences of the pediatric participant. However, 1 project describes a website that will allow children 13 to 17 years of age to set their preferences for return of research results along with their parents.29Kohane I.S. Mandl K.D. Taylor P.L. Holm I.A. Nigrin D.J. Kunkel L.M. Reestablishing the researcher-patient compact.Science. 2007; 316: 836-837Crossref PubMed Scopus (116) Google Scholar Although not described in its consent document, this project plans to return results only when both the adolescent and the parent agree to receive the results. The classification of results as returnable should be based on the consensus of national and local experts and on the priorities and resources of the local biorepository. The decision to actually return such a result to an individual participant, however, should be based whenever possible on the participant's preferences. Ideally, these preferences will be elicited prospectively. For example, some biorepositories use online tools that allow participants to record and change their preferences over time.29Kohane I.S. Mandl K.D. Taylor P.L. Holm I.A. Nigrin D.J. Kunkel L.M. Reestablishing the researcher-patient compact.Science. 2007; 316: 836-837Crossref PubMed Scopus (116) Google Scholar, 30My46 website.https://www.my46.org. Accessed July 12, 2012.Google Scholar Others simply ask participants to record an "all or nothing" preference at the time of enrollment. The challenge of eliciting participant preferences is particularly complex in the setting of pediatric biobanks because investigators must account for the preferences of the parent and those of the pediatric participant.31Avard D. Senecal K. Madadi P. Sinnett D. Pediatric research and the return of individual research results.J Law Med Ethics. 2011; 39: 593-604Crossref PubMed Scopus (32) Google Scholar When it comes to decisions about receiving results for less-mature children, the parent's preferences are determinative. Owing to the complex issues and discussions surrounding returning results, it would be inappropriate to ask the children for their preferences until they are mature enough to understand the relevant implications. When a child is mature enough to weigh the risks and benefits of receiving research results, however, his or her preferences and those of the parent should both be elicited. When both preferences are elicited, conflicts are inevitable. When an adolescent is mature enough to weigh the risks and benefits of receiving research results, the adolescent's preferences should be taken into account and may even outweigh the parent's preferences. In most cases, however, it would still be advisable to return a result only when both the parent and the adolescent agree that the result is wanted.26Presidential Commission for the Study of Bioethical Issues. Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts. Washington, DC; 2013.Google Scholar The authors of a recent recommendation document from the ACMG argued that in the setting of clinical testing, certain secondary findings should be returned even if the patient or parent has declined to receive this information.24Green R.C. Berg J.S. Grody W.W. et al.ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Genet Med. 2013; 15: 565-574Abstract Full Text Full Text PDF PubMed Scopus (1834) Google Scholar However, this particular recommendation was met with significant opposition32Ross L.F. Rothstein M.A. Clayton E.W. Mandatory extended searches in all genome sequencing: "incidental findings," patient autonomy, and shared decision making.JAMA. 2013; 310: 367-368Crossref PubMed Scopus (75) Google Scholar, 33Ross L.F. Rothstein M.A. Clayton E.W. Premature guidance about whole-genome sequencing.Per Med. 2013; 10http://dx.doi.org/10.2217/pme.13.51Crossref PubMed Scopus (9) Google Scholar, 34Klitzman R. Appelbaum P.S. Chung W. Return of secondary genomic findings vs patient autonomy: implications for medical care.JAMA. 2013; 310: 369-370Crossref PubMed Scopus (66) Google Scholar, 35Holtzman N.A. ACMG recommendations on incidental findings are flawed scientifically and ethically.Genet Med. 2013; 15: 750-751Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar and was recently withdrawn by the ACMG.36American College of Medical Genetics and Genomics. ACMG updates recommendation on "opt out" for genome sequencing return of results. https://www.acmg.net/docs/Release_ACMGUpdatesRecommendations_final.pdf. Published April 1, 2014. Accessed April 9, 2014.Google Scholar In addition, ethically relevant differences exist between research and clinical care. In light of this, it remains unresolved whether there are circumstances when research results should be returned when either the parent or the adolescent has declined to receive them. Our group reflects the experiences of a relatively small number of sites. We acknowledge that our experience may not be representative of that of other investigators who have worked with IRBs and other stakeholders on local biorepositories. We also expect that some experts will interpret the relevant issues differently. Given these limitations, we declined to label these proposals as recommendations or even guidelines but instead consider our proposal to provide guidance. We believe that this guidance carries the limited authority that arises from our real-world experience implementing biorepositories in diverse institutions across the country. We hope that this guidance, based on the experience of 9 biobanks at eMERGE Network sites, will facilitate the collaborative work of local stakeholders, including investigators and IRB members, seeking to develop effective informed consent processes for new pediatric biobanks. Through this work, stakeholders have the opportunity not only to contribute to new discoveries in pediatrics but also to help find better solutions to the challenges we discussed. As this guidance document demonstrates, much work remains. A remarkable amount of diversity remains in the way biobanks handle samples from participants who have reached the age of majority, and significant debate remains on how best to return genomic research results, if at all.

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.

PURPOSE:Cataract is the leading cause of blindness in the world, and in the United States accounts for approximately 60% of Medicare costs related to vision. The purpose of this study was to identify genetic markers for age-related cataract through a genome-wide association study (GWAS). METHODS:In the electronic medical records and genomics (eMERGE) network, we ran an electronic phenotyping algorithm on individuals in each of five sites with electronic medical records linked to DNA biobanks. We performed a GWAS using 530,101 SNPs from the Illumina 660W-Quad in a total of 7,397 individuals (5,503 cases and 1,894 controls). We also performed an age-at-diagnosis case-only analysis. RESULTS:We identified several statistically significant associations with age-related cataract (45 SNPs) as well as age at diagnosis (44 SNPs). The 45 SNPs associated with cataract at p<1×10(-5) are in several interesting genes, including ALDOB, MAP3K1, and MEF2C. All have potential biologic relationships with cataracts. CONCLUSIONS:This is the first genome-wide association study of age-related cataract, and several regions of interest have been identified. The eMERGE network has pioneered the exploration of genomic associations in biobanks linked to electronic health records, and this study is another example of the utility of such resources. Explorations of age-related cataract including validation and replication of the association results identified herein are needed in future studies.

Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Genome-wide association studies (GWAS) have identified several loci that contribute to T2D in European Americans, but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in this African American dataset. We were unable to identify novel associations at p<5.0×10(-8) by GWAS. Using admixture mapping as an alternative method for discovery, we performed a genome-wide admixture scan that suggests multiple candidate genes associated with T2D. One finding, TCIRG1, is a T-cell immune regulator expressed in the pancreas and liver that has not been previously implicated for T2D. We performed subsequent fine-mapping to further assess the association between TCIRG1 and T2D in >5,000 African Americans. We identified 13 independent associations between TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11 and T2D. Our results suggest a novel region on chromosome 11 identified by admixture mapping is associated with T2D in African Americans.

Summary Electrocardiographic (ECG) measurements vary by ancestry. Genome‐wide association studies (GWAS) have identified loci that contribute to ECG measurements; however, most are performed in Europeans collected from population‐based cohorts or surveys. The strongest associations reported are in NOS1AP with QT interval and SCN10A with PR and QRS durations. The extent to which these associations can be generalized to African Americans has yet to be determined. Using electronic medical records, PR and QT intervals, QRS duration, and heart rate were determined in 455 African Americans as part of the Vanderbilt Genome‐Electronic Records Project and Northwestern University NUgene Project. We tested for an association between these ECG traits and >930K SNPs. We identified a total 36 novel associations with PR interval, QRS duration, QT interval, and heart rate at p < 1.0 × 10 −6 . Using published GWAS data, we compared our results with those previously identified in other populations. Five associations originally identified in other populations generalized with respect to statistical significance and direction of effect. A total of 43 associations have a consistent direction of effect with European and/or Asian populations. This work provides a catalogue of generalized versus nongeneralized associations, a necessary step in prioritizing GWAS‐identified regions for further fine‐mapping in diverse populations.

Advances in sequencing technology are making genomic data more accessible within the healthcare environment. Published pharmacogenetic guidelines attempt to provide a clinical context for specific genomic variants; however, the actual implementation to convert genomic data into a clinical report integrated within an electronic medical record system is a major challenge for any hospital. We created a two-part solution that integrates with the medical record system and converts genetic variant results into an interpreted clinical report based on published guidelines. We successfully developed a scalable infrastructure to support TPMT genetic testing and are currently testing approximately two individuals per week in our production version. We plan to release an online variant to clinical interpretation reporting system in order to facilitate translation of pharmacogenetic information into clinical practice.

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.

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 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 return of results oversight committee 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 findings of HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of electronic medical records 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. Genet Med 2012:14(4):424–431

Biobanks and archived data sets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings and individual research results of potential health, reproductive, or personal importance to individual contributors (using "biobank" here to refer both to collections of samples and collections of data). This article reports recommendations from a 2-year project funded by the National Institutes of Health. We analyze the responsibilities involved in managing the return of incidental findings and individual research results in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). We suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When reidentification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities to (1) clarify the criteria for evaluating findings and the roster of returnable findings, (2) analyze a particular finding in relation to this, (3) reidentify the individual contributor, and (4) recontact the contributor to offer the finding. We suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and are clinically actionable should generally be offered to consenting contributors. This article specifies 10 concrete recommendations, addressing new biobanks as well as those already in existence.

The Clinical Pharmacogenomics Service (CPS) at Boston Children's Hospital (BCH) was established to use genomic information to make pediatric medications safer. Nearly one-quarter of outpatients are prescribed one or more drugs with genetic information in the FDA label [1]. However, there are still important barriers that must be overcome for routine pharmacogenomic (PGx) clinical use: (1) identification of clinically significant variants, (2) knowledge of variant genotype prior to prescribing medication, and (3) integration with current electronic health record (EHR) systems. To tackle these challenges at BCH, the CPS decided to standardize thiopurine S-methyltransferase (TPMT) testing hospital-wide. TPMT is best known for its role in the catalyzing the S-methylation of the thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. Approximately 13% of Caucasians and African Americans are heterozygous and have reduced TPMT activity, while approximately 0.3% are completely deficient. Defects in the TPMT gene can lead to decreased methylation and excessive levels of the toxic thioguanine nucleotides, particularly with azathioprine and 6-mercaptopurine, and are at risk for bone marrow suppression. Although the FDA drug label recommends testing for TPMT deficiency prior to dosing and the PharmGKB CPIC group published a guideline [2] with a recommended dosing strategy and interpretation, testing is not universal because these guidelines are difficult to translate into a clinical decision support (CDS) system and integrate with the EHRs. We developed models and specifications to execute PGx CDS rules based on a patient's genotype. Rules are modeled at four levels of abstraction: (1) unstructured (narrative), (2) semi-structured, (3) structured, and (4) executable. As genomic sequencing becomes routine, standardized methods to interpret the data and make clinical decisions are paramount. In conjunction with the BCH DNA Diagnostic Laboratory, we streamlined the TPMT testing process to fit into the usual clinical routine (including ordering, testing in-house and return of results to the clinician). We consolidated all genetic sequencing testing into a single clinical workflow (blood to report) that is run, analyzed and interpreted in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory using the codified CDS rules. The interpretation reports are generated automatically directly from the genotype calls and then manually reviewed for accuracy. Once cleared by the laboratory director, the reports are uploaded into the EHR (Cerner). Specialty flow sheets enable providers to easily view the allele status and interpretation report. We intend to expand the PGx platform to include additional drug/gene pairs.

Introduction The eMERGE (electronic MEdical Records and GEnomics) Network is an NHGRI-supported consortium of five institutions to explore the utility of DNA repositories coupled to Electronic Medical Record (EMR) systems for advancing discovery in genome science. eMERGE also includes a special emphasis on the ethical, legal and social issues related to these endeavors. Organization The five sites are supported by an Administrative Coordinating Center. Setting of network goals is initiated by working groups: (1) Genomics, (2) Informatics, and (3) Consent & Community Consultation, which also includes active participation by investigators outside the eMERGE funded sites, and (4) Return of Results Oversight Committee. The Steering Committee, comprised of site PIs and representatives and NHGRI staff, meet three times per year, once per year with the External Scientific Panel. Current progress The primary site-specific phenotypes for which samples have undergone genome-wide association study (GWAS) genotyping are cataract and HDL, dementia, electrocardiographic QRS duration, peripheral arterial disease, and type 2 diabetes. A GWAS is also being undertaken for resistant hypertension in ≈2,000 additional samples identified across the network sites, to be added to data available for samples already genotyped. Funded by ARRA supplements, secondary phenotypes have been added at all sites to leverage the genotyping data, and hypothyroidism is being analyzed as a cross-network phenotype. Results are being posted in dbGaP. Other key eMERGE activities include evaluation of the issues associated with cross-site deployment of common algorithms to identify cases and controls in EMRs, data privacy of genomic and clinically-derived data, developing approaches for large-scale meta-analysis of GWAS data across five sites, and a community consultation and consent initiative at each site. Future activities Plans are underway to expand the network in diversity of populations and incorporation of GWAS findings into clinical care. Summary By combining advanced clinical informatics, genome science, and community consultation, eMERGE represents a first step in the development of data-driven approaches to incorporate genomic information into routine healthcare delivery.