ASSESSING MEDICAL EXAMINERS CURRENT PRACTICES IN UTILIZING GENETIC TESTING FOR AUTOPSY-NEGATIVE SUDDEN UNEXPECTED DEATH IN THE YOUNG (SUDY)

Transcription

1 ASSESSING MEDICAL EXAMINERS CURRENT PRACTICES IN UTILIZING GENETIC TESTING FOR AUTOPSY-NEGATIVE SUDDEN UNEXPECTED DEATH IN THE YOUNG (SUDY) A Thesis Presented to the Faculty of California State University, Stanislaus In Partial Fulfillment of the Requirements for the Degree of Master of Science in Genetic Counseling By Lauren Moissiy December 2016

2 CERTIFICATION OF APPROVAL ASSESSING MEDICAL EXAMINERS CURRENT PRACTICES IN UTILIZING GENETIC TESTING FOR AUTOPSY-NEGATIVE SUDDEN UNEXPLAINED DEATH IN THE YOUNG (SUDY) By Lauren Moissiy Signed Certification of Approval page is on file with the University Library Janey Youngblom, PhD Department of Biology, California State University, Stanislaus Date Kamer Tezcan, MD Medical Genetics, Kaiser Permanente, Sacramento Date Kelsey McClelland, MS, LCGC Biochemical Genetics, University of California, San Francisco Medical Center Date

3 2016 Lauren Moissiy ALL RIGHTS RESERVED

4 DEDICATION This research is dedicated to Scott Milliken and to Niko Winchell. iv

5 ACKNOWLEDGEMENTS This research could not have been done without the assistance and collaboration of the National Association of Medical Examiners (NAME), especially current president David Fowler, MD, current-past president of NAME, Marcus Nashelsky, MD, and Kathryn Pinneri, MD, member of NAME ad hoc data committee. v

6 TABLE OF CONTENTS PAGE Dedication... Acknowledgements... iv v List of Tables... viii List of Figures... Abstract... ix x CHAPTER I. Introduction... 1 Purpose... 6 II. Methodology... 7 Eligibility and Selection of Study Population... 7 Recruitment Strategy... 7 Sample Size... 7 Procedure... 8 Instrument Development... 9 Data Management and Analysis... 9 III. Results IV. Discussion V. Limitations VI. Future Research VII. Conclusion References Appendices A. Informed Consent and Survey B. Survey Open Responses vi

7 C. List of County and States of Respondents Practice D. Open Responses Limitations for Offering or Facilitating Genetic Testing in Cases of Autopsy-Negative SUDY vii

8 LIST OF TABLES TABLE PAGE 1. Number of cases of autopsy-negative Sudden Unexpected Death in the Young (SUDY) in Number of cases of autopsy-negative Sudden Unexpected Death in the Young (SUDY) between Cases of autopsy-negative Sudden Unexpected Death in the Young (SUDY) for which a sample was specifically stored for genetic testing purposes Cases of autopsy-negative Sudden Unexpected Death in the Young (SUDY) for which participants requested or facilitated genetic testing Respondents evaluate statement from 2013 NAME position paper titled Retaining Postmortem Samples For Genetic Testing Barriers to offering or facilitating genetic testing in autopsy-negative SUDY Communication between medical examiners and others regarding genetic testing or DNA banking viii

9 LIST OF FIGURES FIGURE PAGE 1. Cases of SUDY for which medical examiners store a sample NAME position paper familiarity Medical examiners opinion on standardization of genetic testing Medical examiners knowledge of genetic counselors role in facilitating postmortem genetic testing Medical examiners representation of United States Medical examiners jurisdiction ix

10 ABSTRACT The advent of genetic testing offers a new opportunity to explain an unexpected death in which a medical autopsy reaps no answer; a genetic autopsy. The study s purpose is to explore medical examiners current practices and identify obstacles in retaining samples for and facilitating genetic testing, knowledge of the medical genetics community as a resource, and to contribute insight that may help modify current guidelines for genetic testing in Sudden Unexpected Death in the Young (SUDY). An online survey explored medical examiners personal experiences, practices, and opinions surrounding genetic testing in autopsy-negative SUDY cases for those 40 years of age and younger. National Association of Medical Examiners (NAME) members involved in autopsy investigation as a medical examiner or board certified forensic pathologist in the last five years where eligible to participate. Seventy-one medical examiners and forensic pathologists from various states across the U.S. and Canada participated. Practices for sample retention were inconsistent, and only a minority of participants requested or facilitated genetic testing in all cases of autopsynegative SUDY (5%). This study found significant barriers to offering genetic testing in SUDY cases, with 92% of participants citing at least one barrier- the most common of inadequate funding (80%). The majority of participants were not opposed to the integration of genetic testing to the standardized work up for these cases, with 40% of participants reporting it should be, 43% reporting maybe, and 17% opposing the x

11 standardization. Only 18% of participant felt very knowledgeable about the role a genetic counselor could play in facilitating the post-mortem genetic testing process, with 13% of participants reporting no knowledge. While most medical examiners have had recent experience in requesting or facilitating genetic testing in at least one case of autopsy-negative SUDY, inconsistencies and barriers in practice exist. Important themes to improve family care are adequate funding systems and increased knowledge and communication between medical examiners and the medical genetics community. xi

12 CHAPTER I INTRODUCTION Sudden Unexpected Death in the Young (SUDY) has long been regarded as an indication for a medical autopsy by a medical examiner or forensic pathologist in order to seek an explanation for the death. Sometimes these untimely deaths can be explained by known metabolic disorders that result in a metabolic crisis. Others can be explained by neurogenetic disorders that cause seizures that range in severity and type, and the first episode can be life-threatening. Still, there are a portion of these deaths that are never explained by medical autopsy or other biochemical testing. In the past, family members of the decedent were left to grieve without an explanation for the death. A 1998 paper remarked that multiple studies on grief and bereavement in families following a death have identified sudden, unexpected deaths and deaths of a child as significant factors for more complicated bereavement that can culminate in mental illness. For many individuals, part of the grieving process involves going over the events which led up to the loss again and again as if they could find out what went wrong and put it right (Parkes, 1998). For individuals who can not find out what went wrong by medical autopsy, it is possible that the grieving process may be inhibited. Post-mortem DNA testing can sometimes yield an answer for what went wrong, and thus facilitate the natural process of grieving. Post-mortem DNA testing can also sometimes yield a diagnosis that allows for protective medical care, such as medication use, surgery, or transplant, that can ultimately prevent a death or 1

13 2 morbidity. Sample storage specific for genetic testing purposes at time of medical autopsy is not required by any state in the US. The distinction of sample storage specific for genetic testing versus sample storage for other purposes, such as drug toxicity testing, is important to note because genetic testing requires a specific type of sample type (EDTA blood being the gold standard preference, though tissue samples not fixed with formalin or some other types of preservatives can sometimes be used as well) and sample amount is needed in order to do genetic testing. Genetic counselors are the most qualified healthcare provider to assess a family history and medical history of the deceased individual (typically in consult with a cardiologist) in cases of SUDY. Genetic counselors are also qualified to consider the most appropriate genetic testing to consider. Ultimately, the decedent s family members must be able to understand and integrate the information obtained after genetic testing in order for the process to contribute in a positive manner. A genetic counselor is trained specifically to do this, whereas other medical professionals, such as medical examiners, do not have the training, expertise, or time to do so. Annually, thousands of sudden unexplained deaths in the young (SUDY) occur in the United States (Ackerman et al, 2015). The area of cardiogenetics is an emerging field in genetic counseling due to more recent discoveries of genes involved in cardiomyopathies and channelopathies. With now over 100 sudden deathsusceptibility genes identified, whole exome sequencing (WES) with subsequent targeted gene analysis may represent the new molecular autopsy to investigate

14 3 SUDY. (Ackerman et al, 2015). One particular area of interest is the use of cardiogenetic testing in Sudden Infant Death Syndrome (SIDS) and Sudden Cardiac Death (SCD)/Sudden Unexplained Death Syndrome (SUDS) cases in the young. SIDS is defined as the unexplained death after a thorough investigation, including a complete autopsy and review of circumstances of the death and the clinical history, of a seemingly healthy baby up to 1 year of age. The term SUDS is used to describe the same case but for individuals over the age of 12 months. SCD is often used in combination with SUDS in the literature due to the only slight difference in definition between the two terms, related to whether or not an autopsy was performed, if previous knowledge or suspicions of a cardiac anomaly or condition as the probable cause of death existed, and onset of symptoms prior to the event. While the definition of young SCD/SUDS varies in the literature, for this study s purposes young SCD/SUDS, collectively referred to as Sudden Unknown Death in the Young (SUDY) will be defined as individuals as described above, and up to 40 years of age. Sudden Unexplained Natural Deaths in the Young (SUNDY) is another term used often interchangeably in the literature, which also fits within the study s defined term of SUDY. Studies have shown that SIDS may be related to SCD in some infants (Kaltman et al, 2011). The incidence of SIDS ranges from in 100,000, and emerging data suggest that as many as 10% to 15% of SIDS deaths are associated with functional cardiac ion channelopathy gene variants (Tester, 2009). It has been estimated that approximately 25 35% of autopsy-negative SUD and approximately

15 4 10% of SIDS may stem from mutations in either long QT syndrome (LQTS)- or catecholaminergic polymorphic ventricular tachycardia (CPVT)-susceptibility genes. (Ackerman, 2009). Previously, post-mortem genetic analysis by Sanger sequencing of four major cardiac channelopathy genes revealed that approximately 25% of these autopsy-negative sudden unexplained death in the young (SUDY) cases harbored an underlying mutation (Narula et al, 2015). These individuals were all under the age of 18 years old. More recent literature has established that there are now over 100 sudden death-predisposing cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes (Narula et al, 2015). Some vague recommendations for when to offer genetic testing in SIDS cases exist in the literature, but there is an apparent lack of protocol and more formal guidelines for seamless integration into health care (Lee et al, 2014). Previous literature has focused on addressing the benefits to families of obtaining an answer for why their children were affected with SIDS (Guntheroth et al, 1994). Another study has noted that detection and follow up of familial cases of sudden death is challenging and requires a close multidisciplinary collaboration between different medical disciplines (Kauferstein, 2013). Recent expert consensus documents for the diagnosis and management of inheritable arrhythmias state that the use of a focused molecular autopsy/post-mortem genetic testing should be considered for SCD victims when the presence of channelopathies is suspected and this recommendation has been endorsed by the Association for European Pediatric and Congenital Cardiology (AEPC) in the recent publication of the 2015 European Society of Cardiology

16 5 Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. The most current recommendations for Postmortem Genetic Testing in Sudden Unexpected Death Cases (SUDS/SIDS) were published as the HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in 2011 and developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). The following are the current guidelines: 1. For all SUDS and SIDS cases, collection of a tissue sample is recommended (5 10 ml whole blood in EDTA tube, blood spot card, or a frozen sample of heart, liver, or spleen) for subsequent DNA analysis/genetic testing. 2. In the setting of autopsy-negative SUDS, comprehensive or targeted (RYR2, KCNQ1, KCNH2, and SCN5A) ion channel genetic testing may be considered in an attempt to establish probable cause and manner of death and to facilitate the identification of potentially at-risk relatives and is recommended if circumstantial evidence points toward a clinical diagnosis of LQTS or CPVT specifically (such as emotional stress, acoustic trigger, drowning as the trigger of death). 3. Mutation-specific genetic testing is recommended for family members and other appropriate relatives following the identification of a SUDS-causative mutation in the decedent. In a 2013 position paper that was developed by the National Association of Medical Examiners (NAME) with the assistance of genetic counselors, NAME

17 6 recommends establishing "procedures to facilitate postmortem genetic testing and DNA banking by health care professionals assisting families who have experienced sudden death in young relatives by clarifying proper sample acquisition and storage [with the objective of ensuring] that postmortem samples suitable for DNA banking are retained, allowing at risk family members improved detection of potentially treatable genetic diseases" (Middletown, et al). This paper acknowledges some of the hurdles to providing this service, but offers little in terms of solutions to overcome those hurdles. Purpose The primary purpose of this research is to assess current practices and experiences in utilizing genetic testing for SUDY cases from the perspective of the medical examiner s office. From this information, a comparison of various medical examiner offices across the nation may be evaluated to better understand what contributes to or prevents the use of genetic testing in SUDY. The secondary purpose of this project is to contribute insight that may help modify current guidelines for offering and utilizing genetic testing in SUDY as well as inspire changes to enable the medical examiner s office to work more closely with genetic counselors in a multidisciplinary approach to navigating the process.

18 CHAPTER II METHODOLOGY Eligibility and Selection of Study Population Eligible participants for this study are medical examiners or ABP board certified forensic pathologists who have been involved in autopsy investigation in the last 5 years. Participants who are excluded from this study are medical examiners or ABP board certified forensic pathologists who are currently involved in research for genetic testing of autopsy negative SUDY through an institutional study unless survey questions are answered outside of what the research protocol entails. Recruitment Strategy Participants were recruited through the National Association of Medical Examiners by invitation sent by the NAME administrator through the NAME listserve. The organization has about 750 members. A follow up reminder was sent one week after the initial invitation was sent. Sample Size 71 medical examiners and forensic pathologists from NAME participated in the survey, resulting in n=71. The respondents consisted of medical examiners and forensic pathologists from geographically heterogeneous offices. (See appendix C for a list of the respondent s county and state of practice). This gave a broad picture of current practices and experiences across the United States and within different settings. Ideally, receiving more responses is the most desirable outcome for this 7

19 8 particular study because the goal is to learn about any and all differences in current practices to better assess and address what issues or inconsistencies exist in current practices. Within the realm of research participation of physicians, the response rate of 9.5% is lower than the typical or expected response rate for this population. The typical response rate for physicians is about 15-20% according to the literature exploring physician survey response rates across all disciplines. There is no specific literature that explores medical examiner survey response rate. Based on internal data regarding survey response rate for NAME members, a response rate of 9.5% is within the normal or typical range. Procedure Data was collected through an online survey with both presented answer choices as well as open ended short answers. The whole survey is included in Appendix A. Some of the research questions that the survey explored are: When is genetic testing offered or facilitated in autopsy negative SUDY? What is the process and accessibility of sample storage? What barriers exist to offering genetic testing in autopsy negative SUDY? What is the communication between MEO and the deceased individual's family members or other health care providers surrounding genetic testing? Are medical examiners familiar with the 2013 NAME position paper on Retaining Postmortem Samples For Genetic Testing?

20 9 Each participant provided background information about geographic location, years of experience in the field, and number of autopsy negative SUDY cases seen. Each participant signed an informed consent document prior to taking the survey. Instrument Development Pre-testing of the survey was conducted with assistance of the NAME president and a member of the NAME data committee to assess clarity of wording and flexibility of answer choices. Pilot testing was performed with the revised survey on three physicians to assess length of time to complete the survey and to gain feedback on the process. Participants time and effort in taking the online survey was not compensated. Following data analysis and review, a report of the survey results was sent to the NAME data committee and shared with the NAME members, distributed through NAME. Data Management and Analysis IRB approval was obtained from California State University, Stanislaus. The IRB protocol number is # Qualtrics was used to distribute the online survey. Each survey was given a unique identifying code. Study participants surveys were de-identified and survey information was password protected and encrypted. One year after final publication data will be destroyed. Predictive Analytics Software Statistics SPSS program, version 23 was used to enter survey responses into spreadsheets and compute exploratory data analysis and descriptive and inferential statistics from the responses. Quotations from open-ended question answers that

21 exemplify key themes that emerged from the data are included in the presentation of the analysis, as well as all open response answers in the appendices. 10

22 CHAPTER III RESULTS The majority of respondents (56.98%) completed the survey in 4 minutes. This was in-line with the expected time to complete the survey based on the pilot testing that was performed. During pilot testing, it took the respondents between 3-5 minutes to complete the survey. The actual respondents time to complete the survey was in line with the pilot testing results. Table 1. Number of cases of autopsy-negative Sudden Unexpected Death in the Young (SUDY) in 2015 Number of cases Percentage of respondents Number of respondents % % % % % % % 5 Total 100% 70 11

23 12 Out of 70 total responses, 87% of respondents had encountered at least one case of autopsy-negative Sudden Unexpected Death in the Young (SUDY) in the year % of respondents had encountered 1-3 cases, 16% of respondents had encountered 4-6 cases, 9% of respondents had encountered 7-9 cases, 9% of respondents had encountered cases, 3% of respondents had encountered cases, and 7% of respondents had encountered 15 or more cases. Table 2. Number of cases of autopsy-negative Sudden Unexpected Death in the Young (SUDY) between Number of cases Percentage of respondents Number of respondents % % % % % % % 24 Total 100% 70 When respondents were asked to recall how many cases of autopsy-negative SUDY they encountered in the last 5 years, , the amount of cases increased, as expected. Almost every respondent (97%) had seen at least one case of autopsy

24 13 negative SUDY in the last 5 years. 13% of respondents had encountered 1-3 cases, 21% of respondents had encountered 4-6 cases, 13% of respondents had encountered 7-9 cases, 7% of respondents had encountered cases, 9% of respondents had encountered cases, and 34% of respondents had encountered 15 or more cases. When asked if respondents had ever specifically stored a specimen specifically for genetic testing in the cases of autopsy-negative SUDY, 88% of 69 total respondents said that they had. This did not specify if they had stored a specimen for every case. Table 3. Cases of autopsy-negative Sudden Unexpected Death in the Young (SUDY) for which a sample was specifically stored for genetic testing purposes Amount of cases Percentage of respondents Number of respondents All 42.62% 26 Most 31.15% 19 Some 24.59% 15 None 1.64% 1 When asked to recall for how many cases they had stored a sample, 61 respondents answered. Only 43% of respondents said that they stored a sample for all cases of autopsy-negative SUDY, 31% of respondents stored a sample for most cases of autopsy-negative SUDY, 25% of respondents stored a sample for some cases of autopsy-negative SUDY, and 2% (1 respondent) said they did not store a sample for

25 14 any cases of autopsy-negative SUDY. The breakdown of consistency in sample storage for cases can be seen visually in Figure 1 with percentages of cases represented in the figure (n=69). Figure 1. Cases of SUDY for which medical examiners store a sample For those that stored a sample in all cases, 15 respondents came from small counties (population less than 1 million people) and 8 respondents came from large counties (population greater than 1 million people), showing a statistically significant relationship between county size and always storing a sample, with it being nearly twice as likely for samples to be always stored if done in a jurisdiction within a small county. 3 small counties and 3 large counties saw over 15 cases of autopsy-negative SUDY in the last 5 years and always stored a sample for these cases.

26 15 When asked if they had ever requested or facilitated genetic testing in cases of autopsy-negative SUDY, 59% of the 69 respondents responded that they had and 41% of respondents said that they had not. Table 4. Cases of autopsy-negative Sudden Unexpected Death in the Young (SUDY) for which participants requested or facilitated genetic testing Amount of cases Percentage of respondents Number of respondents All 4.88% 2 Most 17.07% 7 Some 78.05% 32 None 0.0% 0 For the 41 respondents whom had requested or facilitated genetic testing in cases of autopsy-negative SUDY, about 78% of them had done so in some cases, compared to about 17% who had done so in most cases, and almost 5% who had done so in all cases. The 2 respondents comprising the nearly 5% who responded with the answer of requesting or facilitating genetic testing in all cases of autopsy-negative SUDY came from a jurisdiction under the other category-those being a private practice in Polk, Tennessee, and a Sheriff-Coroner s Office in Santa Cruz, California.

27 16 Table 5. Respondents evaluate statement from 2013 Name Position Paper titled Retaining Postmortem Samples For Genetic Testing Response Percentage of respondents Number of respondents Strongly agree 46.48% 33 Agree 30.99% 22 Somewhat agree 16.90% 12 Neither agree nor disagree 2.82% 2 Somewhat disagree 0.00% 0 Disagree 0.00% 0 Strongly Disagree 0.00% 0 Unsure 2.82% 2 71 respondents evaluated the statement from the 2013 position paper titled Retaining Postmortem Samples For Genetic Testing which reads It is important to store a specimen, particularly 5-10 ml of blood collected at autopsy that is preserved with K 2 EDTA, for the possibility of performing genetic testing or DNA banking, initiated either by the MEO or through outside source, in all autopsy-negative SUDY. and were asked to choose if they strongly agreed, agreed, somewhat agreed, somewhat disagreed, disagreed, strongly disagreed, neither agreed nor disagreed, or were unsure in regards to the statement. This statement was pulled directly from the 2013 NAME position paper titled Retaining Postmortem Samples For Genetic Testing. In response to the statement, 46% of respondents strongly agreed, 31% of respondents

28 17 agreed, 17% somewhat agreed, 3% of respondents neither agreed nor disagreed, and 3% of respondents were unsure. No respondents somewhat disagreed, disagreed, or strongly disagreed with the statement. Figure NAME position paper familiarity Of 70 total respondents, 74% (52/70) were familiar with the 2013 NAME position paper: Retaining Postmortem Samples For Genetic Testing and 26% (18/70) were not familiar with the paper.

29 18 Table 6. Barriers to offering or facilitating genetic testing in autopsy-negative SUDY response Percentage of respondents Number of respondents Not enough time in work 8.45% 6 day Space limitation for 35.21% 25 storage Inadequate equipment for 15.49% 11 sample retention or storage Difficulty obtaining 5.63% 4 sample Inadequate funding 80.28% 57 Unable to obtain consent 15.49% 11 from remaining family member(s) Unsure of process 15.49% 11 Other 9.86% 7 None 8.45% 6 When asked about what barriers to offering or facilitating genetic testing in cases of autopsy-negative SUDY respondents had encountered, multiple barriers were cited. Overall, 92% of 71 respondents cited at least one barrier to offering genetic testing in cases of autopsy-negative SUDY existed, whereas 8% of respondents cited no barriers existed. Among the barriers listed to choose from, 80% of respondents reported inadequate funding, 35% of respondents reported space limitation for storage, 15% of respondents reported inadequate equipment for sample retention or storage, 15% of respondents reported unsure of process, 15% of respondents reported

30 19 unable to obtain consent from remaining family member, 10% of respondents cited other, 8% of respondents reported not enough time in work day, and 6% of respondents reported difficulty obtaining sample. The 10% of respondents citing other had the opportunity to fill in a response by free text and the responses included No funding and no access to genetic counselors / others to assist and triage, Cost of exam limited to family paying for it, There is not a good referral network and the testing is extremely expensive for those with bad/no insurance, Financial cost of testing, Coroner system. do not have direct access to families, Delay in finding out negative testing results and then no way to obtain sample, and It is not always evident at the time of autopsy that this will be a consideration. Information is often limited, or another mechanism of death appears likely.

31 20 Table 7. Communication between medical examiners and others regarding genetic testing or DNA banking response Percentage of respondents Number of respondents Deceased individual's 74.29% 52 family members Deceased individual's 25.71% 18 primary care provider Genetic counselors 11.43% 8 Medical geneticists 12.86% 9 Other medical examiners 18.57% 13 Genetic testing laboratory 18.57% 13 Other 11.43% 8 None 15.71% 11 When asked if respondents communicated with other persons or resources regarding autopsy-negative SUDY cases and offering genetic testing or DNA banking, 84% of the 70 respondents communicated with at least one individual or resource. 24% of the 70 respondents communicated with a genetic counselor or medical geneticist. The type of communication was not specified in the survey, but likely could include , phone, or in-person correspondence. For those that answered with Other, these responses included coroner (3 total responses), State funded organization with grant to do DNA testing on autopsy negative Sudden Deaths in the Young, We often refer these cases to a local genetic arrhythmia center, I have communicated to

32 21 these individuals the recommendation to investigate genetic testing, and consulting physicians. Figure 3. Medical examiners opinion on standardization of genetic testing When asked if respondents thought genetic testing on autopsy-negative SUDY cases should become a standard part of the routine autopsy work up, i.e. a molecular autopsy, 43% of individuals said yes, 40% of individuals said maybe, and 17% of individuals said no. A one-way ANOVA was performed to evaluate that statistical significance, if any, for answering yes, maybe, or no to the question as related to the respondent s amount of years since board certification. There was no statistically significant differences between group means as determined by the one way ANOVA (F(2,69) = 7.384, p=0.16. Based on grouping respondents by their respective answer, the mean years since board certification for respondents answering yes, maybe, or no were 16.8 years, 16.4 years, and 15 years respectively.

33 22 Figure 4. Medical examiners knowledge of genetic counselors role in facilitating post-mortem genetic testing In assessing the respondents understanding of the role a genetic counselor could play in facilitating post mortem genetic testing in autopsy-negative SUDY cases, the answers varied with no clear majority. 35% of respondents rated themselves as limitedly knowledgeable, 34% of respondents rated themselves as moderately knowledge, 18% of respondents rated themselves as very knowledgeable, and 13% of respondents rated themselves as not knowledge. Nearly half (48%) of respondents rated their knowledge of a GC s role in facilitating post-mortem genetic testing as not knowledgeable or limitedly knowledgeable.

34 23 Respondents represented 29 states and Canada for the location of their current work as medical examiners (see Appendix C for complete list of states and breakdown). Figure 5. Medical examiners representation of United States This map visualizes the number of respondents from each state. The color green represents 1 respondent, blue represents 2 respondents, red represents 3 respondents, yellow represents 4 respondents, orange represents 5 respondents, and purple represents 8 respondents.

35 24 The majority (72%) of respondents worked in a medical examiner s office, 19% of respondents worked in a coroner s Office, and 9% of respondents worked in a other jurisdiction, such as private practice, university, private academic hospital contracted by coroners, or Sheriff-Coroner. Figure 6. Medical examiners jurisdiction The majority (53%) of respondents worked in a jurisdiction of a small county or counties (less than 1 million people), 29% of respondents worked in a jurisdiction of a large county (more than 1 million people), and 18% of respondents reported working in a other size jurisdiction, such as the entire state, multiple counties with a jurisdiction greater than 1.5 million, and half the state. Most (93%) of respondents were board certified in Anatomic and Clinical Pathology and Forensic Pathology and

36 25 7% of respondents were board certified in Forensic Pathology. The mean years since receiving first board certification for respondents was 16 years. Thematic analysis of the optional comments section revealed that cost of testing and funding would be a barrier for offering genetic testing in these cases, with 12/21 open responses including the theme of cost or funding concern as a barrier. Example responses that represented many others include "Either funding or availability of inexpensive tests is needed" and "The cost of the genetic testing was always the issue. The County ME Office was not funded to pickup the cost (thousands of dollars). Some wanted to know and had the funds, some wanted to know but only if someone else paid, some didn't care or were satisfied with the current statistical odds that the sudden death was related to genetics." These quotations highlight the two major aspects of funding as an issue-the high cost of genetic testing and the lack of funding for medical examiner offices in general, not just specifically for genetic testing. Also, questions and opinions about who should pay for the genetic testing in these cases were revealed. Generally, the comments included willingness or desire to perform testing, for example, In my view, we should be doing much more genetic testing than we currently do, while also noting the hurdles to doing so ME offices are challenged by resources and in order to get benefit from molecular autopsies in SUDY cases, would need funding to test, contract with medical geneticists to interpret (including filing an official report and being available to testify in legal proceedings) and convey results to families and other stakeholders, and

37 26 supplies/storage materials. An outlier to the theme of funding was the following response, "Taxpayers should not foot the bill for natural disease related testing", which differed from the general expression that funding was simply an issue. This is also an interesting assertion, considering natural disease related testing (outside of genetic testing) is routinely performed during an autopsy. The option of providing input regarding the survey topic as additional comments was offered at the end of the survey. The response rate for this optional commentary was 21/71 (30%) of respondents. The response types varied from minimal feedback about the survey design, for example a response of, great survey!, to a paragraph that included the respondent s overall approach and opinion on the subject, with example response of, "I STRONGLY believe that in every case possible a purple top tube should be saved - there is NO excuse for not doing that. It is not expensive and does not take up much storage room in the cooler or freezer. That allows the family to at least have the option of getting genetic testing. I do not believe it is likely that most ME offices will in the near future be able to afford to include the genetic testing as part of what the ME does. We can barely afford the tests we do now (histology, tox, etc.) However through developing relationships with local knowledgeable cardiologists and genetic counselors, it is possible to get families the help and information they need. It makes much more sense for families to get testing on their loved one in the context of genetic counseling and a holistic evaluation by a cardiologist, rather than just have a ME do some random genetic tests. We do not know how to interpret those results, nor how to best share that information with

38 27 family members, in my opinion." For further breakdown of the themes that emerged from responses, 3/21 (14%) of respondents expressed positive feedback of the survey, 3/21(14%) of respondents expressed interest in offering genetic testing or sample storage in these cases, and 3/21(14%) of respondents expressed desire for collaboration with other medical professionals.

39 CHAPTER IV DISCUSSION The results showed that there are many differences in opinion and practice among medical examiners in the United States when considering and presented with an autopsy-negative case of SUDY. There are inconsistencies in practice of sample retention for these cases, namely in regards to type of sample stored, and how consistently samples are stored for cases of autopsy-negative SUDY, ranging from never stored to always stored. The study s finding of it being nearly twice as likely for samples to be always stored if done in a jurisdiction within a small county may be due to lower volume of cases per medical examiner, but this was specifically evaluated in the study by asking the participant to recall the number of autopsynegative SUDY cases in the last 1 and then the last 5 years, the range in numbers of cases did not differ significantly comparing large counties and small counties who always stored a sample for these cases. In fact, just as many small counties as large counties saw over 15 cases of autopsy-negative SUDY in the last 5 years. Interestingly, the two respondents who responded with the answer of requesting or facilitating genetic testing in all cases of autopsy-negative SUDY came from a private practice in Polk, Tennessee, and a Sheriff-Coroner s Office in Santa Cruz, California, both practicing in small counties of less than 1 million people and both reporting only 1-3 cases of autopsy-negative SUDY in the last 5 years. Further investigation of these counties and states did not elucidate any policies or regulations 28

40 29 for the practice of genetic testing in these cases. More likely to explain why these two particular respondents always stored a sample for genetic testing in these cases is the smaller volume of cases allowing potentially for more manageability of responsibility, their familiarity with the NAME position paper (both responded that they were familiar with the paper and both strongly agreed with the statement regarding the importance of sample storage for these cases, which had come directly from the NAME position paper) and their response of no barriers to genetic testing exist in their practice. Surprisingly, one of these respondents rated their knowledge of a genetic counselor s role in facilitating genetic testing in these cases as limitedly knowledgeable and the other respondent rated it as moderately knowledgeable. This is consistent with the overall findings related to relationship between the NAME position paper familiarity and knowledge of the genetic counselor s role, discussed further here. Genetic counselors are vital providers in deciding which genetic testing is most appropriate, possibly finding alternate ways of facilitating genetic testing if cost is an issue, and for the decedent s family to understand and integrate the information obtained through post-mortem genetic testing. There exists a lack of knowledge of what a genetic counselor s role might look like in facilitating genetic testing for medical examiners, as most medical examiners who responded did not identify themselves are being knowledgeable beyond a small amount. Interestingly, most medical examiners had responded that they were familiar with the 2013 NAME position paper that explains and provides the knowledge about what a genetic

41 30 counselor can do to assist medical examiners in caring for the decedents in cases of SUDY. Based on this finding, it seems that further education is needed to encourage a multidisciplinary approach to care. While a position paper is an important contribution to the subject, it is not truly sufficient to educate the medical examiners community on this topic. Other tactics or strategies may need to be employed, such as forming connections with local genetics community through in person presentations, brochures being distributed to the medical examiners offices with a genetic counselor contact or a website link to the National Society of Genetic Counselor s website. Another idea is to make webinars on the subject geared towards genetic counselors and/or medical examiners, which could be done with genetic counselors input as well as medical examiners input. There are also multiple barriers to offering or facilitating genetic testing within a medical examiner s office or other jurisdiction. While financial constraints were largely cited as a barrier, there are also other barriers to face even if financial constraints could be addressed. Space limitations for storage is a barrier that could potentially be solved by using blood spots on Guthrie paper as samples as opposed to tubes of blood, since that would require less space. However, at this point in time, genetic testing on blood spots is not something that all laboratories will perform, though the technology for the testing exists. Related to that, often there is only enough blood on a blood spot card to perform one genetic test. This can create a dilemma for genetic counselors, as well as remaining family members, about balancing the risk and trade off of doing genetic testing. For example, a dilemma may

42 31 be that the family could immediately benefit from learning of positive test results so that other family members could be tested and screened, but the immediately available testing is limited by the current knowledge of known genes and variants associated with hereditary disease. Waiting a few years or more might mean new genetic knowledge, but might also mean losing the opportunity to help or even safe a family member s life in the meantime. Many medical examiners did not understand what type of sample would be best to store and how to store the sample for these cases. Besides providing educational material through an online published position paper, it may be worthwhile to consider training medical examiners specifically for how to deal with these cases of SUDY. This training may be done through a webinar or online course, or integrated into the annual meeting for NAME. Training for medical examiners may include ensuring that the individual understands the value of retaining an adequate sample in these specific cases, what the protocol for sample retention is, and also making sure that the medical examiners know that they may request assistance from a genetic counselor for clarification if needed. Providing the medical examiner with a contact for a genetic counselor would be paramount. It would also be useful for medical examiners, once trained, to be able to communicate the need to retain proper sample and storage to others within the medical examiner s office, such as with lab technicians and front end staff. Attempting to test out if something like this could potentially be applied could at first be tested with a smaller

43 32 case selection, such as doing so specifically in SIDS or SUD in children 2 years and under. Genetic counselors likely would also benefit from additional training. Though not studied in this research project, other research exists that has identified inconsistencies or lack of knowledge for how to approach these types of cases. Training for genetic counselors may include how to work with medical examiners. This could be implemented into the genetic counseling graduate training curricula and also provided through webinars or at educational conferences, such as the annual educational conference for the National Society of Genetic Counselors. It would also be useful to prepare genetic counselors for what questions medical examiners may ask of them during communication about these cases. Also, it would be worthwhile to prepare genetic counselors for what questions to ask the medical examiners regarding the sample in question to ensure that the sample is a worthwhile candidate for genetic testing, rather than wasting time and financial resources for pursuing testing. Emotionally, it could be very burdensome for both the genetic counselor and the decedent s family if an expectation of being able to pursue genetic testing is set for the family members and then the genetic counselor is forced to take the hope away due to lack of correct or available sample for genetic testing. Though the steps towards incorporating a change or addition to the American Board of Genetic Counselors examination may present as hurdles and be timeconsuming, an idea is to have a question on the test regarding what the most appropriate steps for communicating and working with medical examiners would be.

44 33 This may encourage both genetic counselors and the genetic counseling graduate program directors to actively include this topic in their training. Medical examiners generally are open to the possibility of integrating genetic testing into their work-up, based on the assumption that those who responded as maybe the molecular autopsy should become standardized are at least willing to consider it. The thematic analysis that revealed opinions and questioning about how testing could or would be funded and who should pay for it bring up an interesting point. The concept of whether or not a molecular autopsy should fall on taxpayers begs the question of what is considered a public health concern. The typical or standard medical autopsy currently falls on taxpayers financing. For some families of decedents, a private practice is used in order to have a medical autopsy performed and this is paid for by the family. Newborn screening in states across the U.S. also is financed by taxpayers, which is an interesting comparison in terms of utility of genetic testing and public health concerns. One could argue that there is overlap in utility of genetic testing with future hopes of screening all individuals for rare variants that can cause SUDY. As noted by Weyhrauch, et al. in a 2015 study, there are thousands of sudden unexplained deaths in the young (SUDY) in the United States each year. There are also now over 100 sudden death-susceptibility genes identified to date. Utilizing genetic testing may be able to identify disease-causing variants in up to 20% of cases of SUDY, which could subsequently be used for predictive variant-specific testing for the decedent s surviving relatives. This predictive testing would allow for potentially

45 34 life-saving and morbidity-reducing medical management of the decedent s surviving relations. Weyhrauch et. al. explored use of whole exome sequencing (WES) with subsequent targeted gene analysis to represent a new molecular autopsy to investigate SUDY. While WES may be financially more burdensome, either for taxpayers or families who pay out of pocket for testing, panel testing could potentially allow comparable or at least worthwhile yields in identification of disease-causing variants. Comments from respondents in the optional response section mentioned that the decedents family members were typically contacted about the option to pursue genetic testing on the deceased individual. Unfortunately, it is likely outside the scope of a medical examiner to know which type of genetic testing to order or recommend. While it is important that a medical examiner make the first step in contacting the families about the option for genetic testing, a genetic counselor would likely be the most informed provider for genetic test selection. Also, a genetic counselor would be useful for preparing individuals for expectations of genetic testing, as well as interpretation of genetic test results. Comments from respondents in the optional response section also noted the benefit of having other genetic experts involved in order to facilitate genetic testing and interpretation.

46 CHAPTER V LIMITATIONS With the response rate of 9.5%, there may be a bias in the results due to a low response rate. One must also take into consideration that there may be a response bias toward medical examiners or forensic pathologists that saw the survey invitation and responded because they were interested in the topic and/or had experience with the topic. Future research in this arena would be useful in order to gain a deeper understanding of current practices within medical examiners offices. Those with a stronger interest in the subject of genetic testing and/or SUDY may have been more motivated to take the survey. It is notable that there were a portion of respondents (13%) who took the survey and had not encountered a case of SUDY in the last 5 years, which could possibly mean that there was not a total bias of response from individuals having interest in the topic stemming from experience with the topic. It still is possible that those respondents had an interest in the topic outside of their experience in the last 5 years. Taking into consideration that medical examiners may have a heavy workload, the survey was designed to be short in length and simple to answer. The survey was designed this way to encourage more medical examiners to take the survey, with the hope that dedicating a smaller amount of time would be more manageable and appealing. However, some arguably important questions, such as how long samples are stored at the facility if they are stored, were not included and 35

47 36 thus a limitation of this study. Knowing how long samples are stored at the facility is important to the topic of this study because there must be a reasonable amount of time for the remaining family members of the deceased individual to learn about genetic testing or DNA banking as an option. If a sample is taken but disposed of after a few months, this may not be sufficient time for family members to learn about and organize the genetic testing or DNA banking. Unfortunately, anecdotal evidence has shown this to be a reality at times.

48 CHAPTER VI FUTURE STUDIES This study was a way of getting a foundation of understanding of current practices among medical examiners. More detailed understanding of current practices could be explored, possibly specifically for each state. Exploring how this topic is addressed in other countries, such as Canada, where the healthcare system is provided by the government, could also be insightful for what practices are effective or not effective. The financial value of post-mortem genetic testing in these cases is another important topic to explore when addressing the topic from a public health standpoint. This is a topic that would require a more intensive examination of the topic that may be outside the scope of a master s degree research thesis, though perhaps something that could be taken on by more than one master s candidate. Future research comparing the medical examiners perspective and the decedent s family perspective of the process could also be explored in order to better formulate ideas or guidelines for medical examiners and those who care for and help decedents families navigate the process (such as genetic counselors and support group organizations). This could be done through quantitative or qualitative survey. Qualitative research may add a new dimension to this research, especially through use of focus groups of families who have experienced SUDY. SADS is a group that could potentially be useful for future studies in order to get in contact with families who have been affected by a SUDY in their family, especially in consideration of a qualitative study. 37