Pediatr Blood Cancer 2015;62:1374–1380
Overcoming Challenges to Meaningful Informed Consent for Whole Genome Sequencing in Pediatric Cancer Research Jennifer A. Oberg, EdD, MA,1 Julia L. Glade Bender, MD,1 Elizabeth G. Cohn, RN, DNS,2 Marilyn Morris, MD, MPH,3 Jenny Ruiz, BA,4 Wendy K. Chung, MD, PhD,5 Paul S. Appelbaum, MD,6 Andrew L. Kung, MD, PhD,1 and Jennifer M. Levine, MD, MSW1* Background. Introducing whole genome sequencing (WGS) into pediatric cancer research at diagnosis poses unique challenges related to informed consent. WGS requires tissue obtained prior to initiating treatment, when families may be overwhelmed with uncertainty and fear. Motivation to participate may be high without fully understanding the range of possible results, including secondary findings. Little is known about parental knowledge, attitudes, and beliefs about this type of research. Procedure. A qualitative study was conducted to investigate parental knowledge about genetic concepts and WGS, thoughts about the informed consent process, and preferences for secondary findings. Focus groups were conducted with parents/guardians of children with cancer and semi-structured interviews were conducted in a control group without cancer. All transcripts were analyzed using content analysis. Results. Four focus groups included 15 participants; eight semi-structured interviews
included 10 participants. Basic knowledge about genetics was limited to heredity. Some knowledge of genomic analysis was present in 3/15 focus group participants. Major factors related to participation in WGS research were: (i) hope for their child and future children; (ii) no additional procedures; (iii) and protection of privacy. All favored a two-step consent process, first to store extra tissue from a diagnostic biopsy/resection, followed by consenting to WGS research, one-totwo months later. The desire to receive secondary findings was high among both groups, but there were individuals who did not want these results, fearing increased anxiety. Conclusions. Parents/guardians of children with cancer have limited knowledge about WGS. A two-step consent process may improve their ability to provide meaningful informed consent. Pediatr Blood Cancer 2015;62:1374– 1380. # 2015 Wiley Periodicals, Inc.
Key words: informed consent; pediatric oncology; whole genome sequencing
INTRODUCTION Whole-genome sequencing (WGS) provides the most comprehensive view of the genome and is increasingly being explored for clinical use by pediatric oncology researchers across the country. WGS research conducted by a CLIA compliant lab to guide precision cancer therapy is predicated on the notion that comparison of tumor and normal tissue will identify targetable somatic variants leading to improved clinical outcomes through selection of more effective, less toxic treatments [1]. However, the technology presents challenges related to identification, interpretation, and return of clinical- grade somatic and germline results. Specifically, somatic mutations currently include only a few medically actionable variants and a large number of variants of unknown significance [2]. Non-cancerous germline disease-causing mutations and germline cancer susceptibility mutations, referred to as secondary findings, may also be identified [3]. Furthermore, secondary findings may be present in other family members not involved in the research [4,5]. These aspects of genomic research raise pragmatic and ethical dilemmas including defining essential components of the informed consent process, determining what types of results should be returned, whether patients should have a role in making this determination, and what types of data should be incorporated into medical records [6-11]. Obtaining consent for WGS research from parents of children with newly diagnosed cancer poses additional challenges to those outlined above. Given the high efficacy of standardized treatment protocols for the majority of pediatric cancer patients [12], there is only a small chance that initial therapy will be altered by WGS research. In addition, tissue for sequencing should be obtained prior to initiating therapy, a time when patients and parents often feel overwhelmed with uncertainty and fear. With hopes for a cure, parental motivation to participate in WGS research may be high without fully understanding the range of results that may be C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25520 Published online 1 April 2015 in Wiley Online Library (wileyonlinelibrary.com).
returned, including variants of unknown significance and secondary findings. Conversely, parents may reject participation in studies not directly related to the immediate diagnosis or treatment of their child. These considerations suggest that parents of children newly diagnosed with cancer will need to understand WGS and its consequences to make informed decisions before participating in research [13,14]. In anticipation of launching a pediatric precision medicine program, with an emphasis on WGS, for all newly diagnosed cancer patients, we explored challenges to informed Additional Supporting Information may be found in the online version of this article at the publisher’s web-site. 1 Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York; 2School of Nursing, Division of Academics, Columbia University Medical Center, 161 Fort Washington Avenue, IP7, New York, New York; 3Department of Pediatrics, Division of Pediatric Critical Care, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York; 4College of Physicians and Surgeons, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York ; 5Department of Pediatrics and Medicine, Division of Pediatric Molecular Genetics, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York; 6Department of Psychiatry, Division of Law, Ethics, and Psychiatry, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York
Conflict of interest: Nothing to declare. Correspondence to: Jennifer M. Levine, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Medical Center, 161 Fort Washington Avenue, IP7, New York, NY 10032. E-mail: [email protected]
Received 22 August 2014; Accepted 19 February 2015
Parents and Whole Genome Sequencing Research consent and propose elements to consider when approaching the consent process for WGS research in pediatric oncology.
METHODS Participants Focus groups were conducted in a “cancer-exposed” group with parents/guardians of children with cancer at any point in their treatment and with one young–adult cancer patient. Recruitment was conducted on the day of each focus group via general announcement by a research coordinator in the pediatric oncology outpatient clinic at Columbia University Medical Center (CUMC). Since participants were self-selected, no data are available regarding those who chose not to participate. To explore the hypothesis that experiences related to having a child with cancer lead to increased knowledge about genetics in childhood cancer, a control group of parents of children without cancer was included in the study. These “cancer-naı¨ve” parents were chosen as a proxy for parents of children with newly diagnosed cancer who may not be familiar with genetics and the role of genetics in guiding treatment. This cohort included parents of generally healthy children admitted to the pediatric medical/ surgical inpatient units for non-life threatening medical reasons. Only one parent declined participation. Since focus groups were not practical for this cohort, individual semi-structured interviews were conducted. Participants were required to be English-speaking. Everyone received a $25 gift card as compensation. Study approval was received from the CUMC Institutional Review Board.
Procedures Focus group and interview guides included open-ended questions (Supplementary File I) addressing the following: (i) baseline knowledge of genetic concepts/WGS; (ii) opinions regarding the process and timing for obtaining informed consent for WGS research in childhood cancer; (iii) expectations for WGS research in childhood cancer; and (iv) preferences about the return of secondary findings (defined as risks identified through WGS for other diseases not related to the cancer under study). Standardized explanations of key concepts, including definitions of DNA, genes, and WGS were provided after participants were initially asked about baseline knowledge. The process of using tissue from a diagnostic procedure for WGS research was also explained to both groups. Between June and July 2013, focus groups were conducted by an experienced moderator (EC) in a conference room within the division of pediatric oncology. In August 2013, semi-structured interviews were conducted by a study investigator (JR) in individual inpatient rooms. Written informed consent was obtained and a demographic survey was completed. Focus groups and semistructured interviews were audio recorded and transcribed verbatim by an independent transcription service.
Data Analysis Focus group transcripts were analyzed using content analysis [15] and NVIVO version 10. The initial codebook identified broad themes based on content analysis and a priori hypotheses. Three researchers (EC, JML, JAO) independently read the transcripts for context and meaning, coded the first transcript Pediatr Blood Cancer DOI 10.1002/pbc
1375
line-by-line, and compared results. Discrepancies were resolved by consensus. The process continued for each transcript to identify common themes within which similar codes could be grouped. Quotes illustrating common themes were identified and agreed upon [15,16]. Responses were tallied by group, except when direct questioning allowed for individual responses to be quantified. Thematic saturation was reached in group three. One additional focus group was conducted to ensure that a concern or opinion was not missed. During data analyses, one participant in the final focus group was identified as the guardian of a child without cancer. Based on field notes and comparison of responses we determined the participant’s attendance did not alter the content of the session and the participant was excluded from all analyses. Semi-structured interviews were coded by two researchers (JML, JAO) utilizing the codes identified in the focus groups. No new codes were identified. Individual responses were tallied and aggregated.
RESULTS Focus Groups of Cancer-Exposed Participants A total of 15 cancer-exposed participants, divided among four focus groups (3–6 participants each), were included in the analyses. Participant characteristics are presented in Table I. Racial and ethnic characteristics are representative of the patient population in our pediatric oncology practice and at CUMC. Seventy percent of the participants were female; 80% had at least a high school education; and 60% were parents of children with leukemia or lymphoma. Results were organized into five themes (Figure 1): (i) baseline awareness of genetics and WGS; (ii) factors that might affect the decision to participate in WGS research; (iii) thoughts and attitudes about the informed consent process; (iv) expectations for WGS in childhood cancer; and (v) thoughts and attitudes about returning secondary findings.
Baseline Awareness of Genetic Testing and WGS A majority of focus group participants’ knowledge about DNA, genes, and genetic testing was related to heredity; only one participant distinguished between inherited and acquired mutations. Reported sources of information included books, the internet, news media, and personal experience. Prior knowledge of WGS was identified in 3/15 (20%) participants. In two instances, directed genetic testing was mistaken for WGS.
Factors Affecting the Decision to Participate in WGS Four elements were identified as factors likely to influence participation in WGS research: the prospect of their children benefiting from testing; altruism; understanding that an additional procedure was not required to obtain tissue for research testing; and the degree to which results would be kept private. Hope for participants’ children and for other children with cancer was identified throughout all focus groups as central to the decision to participate. Specifically related to participants’ children was the hope for a cure. “I would have done anything. I would have sold my soul to the devil to make it not be or to find a cure.” (Group 2) The prospect that their children’s participation could help find a cure in the future and benefit other children was also a strong motivating factor.
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Oberg et al.
TABLE I. Participant Demographics Participant Characteristics
Cancer Exposed (n ¼15)
Cancer Naı¨ve (n ¼10)
4 [26.7] 11 [73.3]
3 [30.0] 7 [70.0]
10 [66.7] 2 [13.3] 1 [6.7] — 1 [6.7] — — 1 [6.7]
5 [50.0] 2 [20.0] — 1 [10.0] — 1 [10.0] 1 [10.0] —
9 [60.0] 1 [6.7] 2 [13.3] 1 [6.7] 2 [13.3] — — — — —
4 2 1 1 2
— — — — — [40.0] [20.0] [10.0] [10.0] [20.0]
10 [66.7] 3 [20.0] 1 [6.7] 1 [6.7]
3 [30.0] 3 [30.0] — 4 [40.0]
11 [73.3] 4 [26.7]
6 [60.0] 4 [40.0]
2 [13.3] 3 [20.0] 4 [26.7] 3 [20.0] 2 [13.3] 1 [6.7]
1 4 3 1 1
Gender Male Female Relationship to Child Mother Father Grandmother Great Grandmother Brother Uncle Aunt Self Diagnosis of Child Leukemia/Lymphoma Medulloblastoma Rhabdomyosarcoma HLHa PTLDb Injury Infection Eczema Acute stomach pain Not specified Race White Black or African American Asian Other Ethnicity Non-Hispanic or Latino Hispanic or Latino Education
Overcoming Challenges to Meaningful Informed Consent for Whole Genome Sequencing in Pediatric Cancer Research Jennifer A. Oberg, EdD, MA,1 Julia L. Glade Bender, MD,1 Elizabeth G. Cohn, RN, DNS,2 Marilyn Morris, MD, MPH,3 Jenny Ruiz, BA,4 Wendy K. Chung, MD, PhD,5 Paul S. Appelbaum, MD,6 Andrew L. Kung, MD, PhD,1 and Jennifer M. Levine, MD, MSW1* Background. Introducing whole genome sequencing (WGS) into pediatric cancer research at diagnosis poses unique challenges related to informed consent. WGS requires tissue obtained prior to initiating treatment, when families may be overwhelmed with uncertainty and fear. Motivation to participate may be high without fully understanding the range of possible results, including secondary findings. Little is known about parental knowledge, attitudes, and beliefs about this type of research. Procedure. A qualitative study was conducted to investigate parental knowledge about genetic concepts and WGS, thoughts about the informed consent process, and preferences for secondary findings. Focus groups were conducted with parents/guardians of children with cancer and semi-structured interviews were conducted in a control group without cancer. All transcripts were analyzed using content analysis. Results. Four focus groups included 15 participants; eight semi-structured interviews
included 10 participants. Basic knowledge about genetics was limited to heredity. Some knowledge of genomic analysis was present in 3/15 focus group participants. Major factors related to participation in WGS research were: (i) hope for their child and future children; (ii) no additional procedures; (iii) and protection of privacy. All favored a two-step consent process, first to store extra tissue from a diagnostic biopsy/resection, followed by consenting to WGS research, one-totwo months later. The desire to receive secondary findings was high among both groups, but there were individuals who did not want these results, fearing increased anxiety. Conclusions. Parents/guardians of children with cancer have limited knowledge about WGS. A two-step consent process may improve their ability to provide meaningful informed consent. Pediatr Blood Cancer 2015;62:1374– 1380. # 2015 Wiley Periodicals, Inc.
Key words: informed consent; pediatric oncology; whole genome sequencing
INTRODUCTION Whole-genome sequencing (WGS) provides the most comprehensive view of the genome and is increasingly being explored for clinical use by pediatric oncology researchers across the country. WGS research conducted by a CLIA compliant lab to guide precision cancer therapy is predicated on the notion that comparison of tumor and normal tissue will identify targetable somatic variants leading to improved clinical outcomes through selection of more effective, less toxic treatments [1]. However, the technology presents challenges related to identification, interpretation, and return of clinical- grade somatic and germline results. Specifically, somatic mutations currently include only a few medically actionable variants and a large number of variants of unknown significance [2]. Non-cancerous germline disease-causing mutations and germline cancer susceptibility mutations, referred to as secondary findings, may also be identified [3]. Furthermore, secondary findings may be present in other family members not involved in the research [4,5]. These aspects of genomic research raise pragmatic and ethical dilemmas including defining essential components of the informed consent process, determining what types of results should be returned, whether patients should have a role in making this determination, and what types of data should be incorporated into medical records [6-11]. Obtaining consent for WGS research from parents of children with newly diagnosed cancer poses additional challenges to those outlined above. Given the high efficacy of standardized treatment protocols for the majority of pediatric cancer patients [12], there is only a small chance that initial therapy will be altered by WGS research. In addition, tissue for sequencing should be obtained prior to initiating therapy, a time when patients and parents often feel overwhelmed with uncertainty and fear. With hopes for a cure, parental motivation to participate in WGS research may be high without fully understanding the range of results that may be C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25520 Published online 1 April 2015 in Wiley Online Library (wileyonlinelibrary.com).
returned, including variants of unknown significance and secondary findings. Conversely, parents may reject participation in studies not directly related to the immediate diagnosis or treatment of their child. These considerations suggest that parents of children newly diagnosed with cancer will need to understand WGS and its consequences to make informed decisions before participating in research [13,14]. In anticipation of launching a pediatric precision medicine program, with an emphasis on WGS, for all newly diagnosed cancer patients, we explored challenges to informed Additional Supporting Information may be found in the online version of this article at the publisher’s web-site. 1 Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York; 2School of Nursing, Division of Academics, Columbia University Medical Center, 161 Fort Washington Avenue, IP7, New York, New York; 3Department of Pediatrics, Division of Pediatric Critical Care, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York; 4College of Physicians and Surgeons, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York ; 5Department of Pediatrics and Medicine, Division of Pediatric Molecular Genetics, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York; 6Department of Psychiatry, Division of Law, Ethics, and Psychiatry, Columbia University Medical Center, 161 Fort Washington Avenue IP7, New York, New York
Conflict of interest: Nothing to declare. Correspondence to: Jennifer M. Levine, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Medical Center, 161 Fort Washington Avenue, IP7, New York, NY 10032. E-mail: [email protected]
Received 22 August 2014; Accepted 19 February 2015
Parents and Whole Genome Sequencing Research consent and propose elements to consider when approaching the consent process for WGS research in pediatric oncology.
METHODS Participants Focus groups were conducted in a “cancer-exposed” group with parents/guardians of children with cancer at any point in their treatment and with one young–adult cancer patient. Recruitment was conducted on the day of each focus group via general announcement by a research coordinator in the pediatric oncology outpatient clinic at Columbia University Medical Center (CUMC). Since participants were self-selected, no data are available regarding those who chose not to participate. To explore the hypothesis that experiences related to having a child with cancer lead to increased knowledge about genetics in childhood cancer, a control group of parents of children without cancer was included in the study. These “cancer-naı¨ve” parents were chosen as a proxy for parents of children with newly diagnosed cancer who may not be familiar with genetics and the role of genetics in guiding treatment. This cohort included parents of generally healthy children admitted to the pediatric medical/ surgical inpatient units for non-life threatening medical reasons. Only one parent declined participation. Since focus groups were not practical for this cohort, individual semi-structured interviews were conducted. Participants were required to be English-speaking. Everyone received a $25 gift card as compensation. Study approval was received from the CUMC Institutional Review Board.
Procedures Focus group and interview guides included open-ended questions (Supplementary File I) addressing the following: (i) baseline knowledge of genetic concepts/WGS; (ii) opinions regarding the process and timing for obtaining informed consent for WGS research in childhood cancer; (iii) expectations for WGS research in childhood cancer; and (iv) preferences about the return of secondary findings (defined as risks identified through WGS for other diseases not related to the cancer under study). Standardized explanations of key concepts, including definitions of DNA, genes, and WGS were provided after participants were initially asked about baseline knowledge. The process of using tissue from a diagnostic procedure for WGS research was also explained to both groups. Between June and July 2013, focus groups were conducted by an experienced moderator (EC) in a conference room within the division of pediatric oncology. In August 2013, semi-structured interviews were conducted by a study investigator (JR) in individual inpatient rooms. Written informed consent was obtained and a demographic survey was completed. Focus groups and semistructured interviews were audio recorded and transcribed verbatim by an independent transcription service.
Data Analysis Focus group transcripts were analyzed using content analysis [15] and NVIVO version 10. The initial codebook identified broad themes based on content analysis and a priori hypotheses. Three researchers (EC, JML, JAO) independently read the transcripts for context and meaning, coded the first transcript Pediatr Blood Cancer DOI 10.1002/pbc
1375
line-by-line, and compared results. Discrepancies were resolved by consensus. The process continued for each transcript to identify common themes within which similar codes could be grouped. Quotes illustrating common themes were identified and agreed upon [15,16]. Responses were tallied by group, except when direct questioning allowed for individual responses to be quantified. Thematic saturation was reached in group three. One additional focus group was conducted to ensure that a concern or opinion was not missed. During data analyses, one participant in the final focus group was identified as the guardian of a child without cancer. Based on field notes and comparison of responses we determined the participant’s attendance did not alter the content of the session and the participant was excluded from all analyses. Semi-structured interviews were coded by two researchers (JML, JAO) utilizing the codes identified in the focus groups. No new codes were identified. Individual responses were tallied and aggregated.
RESULTS Focus Groups of Cancer-Exposed Participants A total of 15 cancer-exposed participants, divided among four focus groups (3–6 participants each), were included in the analyses. Participant characteristics are presented in Table I. Racial and ethnic characteristics are representative of the patient population in our pediatric oncology practice and at CUMC. Seventy percent of the participants were female; 80% had at least a high school education; and 60% were parents of children with leukemia or lymphoma. Results were organized into five themes (Figure 1): (i) baseline awareness of genetics and WGS; (ii) factors that might affect the decision to participate in WGS research; (iii) thoughts and attitudes about the informed consent process; (iv) expectations for WGS in childhood cancer; and (v) thoughts and attitudes about returning secondary findings.
Baseline Awareness of Genetic Testing and WGS A majority of focus group participants’ knowledge about DNA, genes, and genetic testing was related to heredity; only one participant distinguished between inherited and acquired mutations. Reported sources of information included books, the internet, news media, and personal experience. Prior knowledge of WGS was identified in 3/15 (20%) participants. In two instances, directed genetic testing was mistaken for WGS.
Factors Affecting the Decision to Participate in WGS Four elements were identified as factors likely to influence participation in WGS research: the prospect of their children benefiting from testing; altruism; understanding that an additional procedure was not required to obtain tissue for research testing; and the degree to which results would be kept private. Hope for participants’ children and for other children with cancer was identified throughout all focus groups as central to the decision to participate. Specifically related to participants’ children was the hope for a cure. “I would have done anything. I would have sold my soul to the devil to make it not be or to find a cure.” (Group 2) The prospect that their children’s participation could help find a cure in the future and benefit other children was also a strong motivating factor.
1376
Oberg et al.
TABLE I. Participant Demographics Participant Characteristics
Cancer Exposed (n ¼15)
Cancer Naı¨ve (n ¼10)
4 [26.7] 11 [73.3]
3 [30.0] 7 [70.0]
10 [66.7] 2 [13.3] 1 [6.7] — 1 [6.7] — — 1 [6.7]
5 [50.0] 2 [20.0] — 1 [10.0] — 1 [10.0] 1 [10.0] —
9 [60.0] 1 [6.7] 2 [13.3] 1 [6.7] 2 [13.3] — — — — —
4 2 1 1 2
— — — — — [40.0] [20.0] [10.0] [10.0] [20.0]
10 [66.7] 3 [20.0] 1 [6.7] 1 [6.7]
3 [30.0] 3 [30.0] — 4 [40.0]
11 [73.3] 4 [26.7]
6 [60.0] 4 [40.0]
2 [13.3] 3 [20.0] 4 [26.7] 3 [20.0] 2 [13.3] 1 [6.7]
1 4 3 1 1
Gender Male Female Relationship to Child Mother Father Grandmother Great Grandmother Brother Uncle Aunt Self Diagnosis of Child Leukemia/Lymphoma Medulloblastoma Rhabdomyosarcoma HLHa PTLDb Injury Infection Eczema Acute stomach pain Not specified Race White Black or African American Asian Other Ethnicity Non-Hispanic or Latino Hispanic or Latino Education
