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Implementation of Molecular Autopsy for Sudden Cardiac Death in Japan ― Focus Group Study of Stakeholders ―
2023 Volume 87 Issue 1 Pages 123-129
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2023 Volume 87 Issue 1 Pages 123-129
Background: We assessed the awareness of multidisciplinary healthcare professionals of the challenges related to implementation of molecular autopsy (MA) for sudden cardiac death (SCD) among children and young adults.
Methods and Results: We conducted 11 focus groups with 31 multidisciplinary healthcare professionals, and categorized them into 2 themes: values, and challenges of MA implementation. The participants recognized 2 different values of MA: discovering the unknown cause of SCD, and SCD prevention among family members of victims. The coexistence of these values makes the MA process and role of professionals more complex. Participants were concerned about the psychological burden for bereaved family members and mentioned challenges in each process of the MA delivery system: obtaining consent, cause of death investigation, disclosing results, and preventive intervention.
Conclusions: MA is a valuable procedure both in terms of forensic and preventive medicine. However, the dual meanings and complex characteristics of genetic information is a potential source of concern and confusion among healthcare professionals as well as bereaved family members. Increasing awareness among healthcare professionals of the MA process is essential for connecting all related areas of expertise.
About 1,500 young people aged 1–35 years die from sudden cardiac death (SCD) each year in Japan.1 A population-based study of SCD among children and young adults showed that unexplained SCDs are caused by undiagnosed hereditary cardiac disorders, such as long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.2–4 These lethal arrhythmias without structural change of the heart cannot be identified by gross autopsy. In fact, the cause of death in 30% of young SCD victims remains unclear after conventional autopsy.5 A molecular autopsy (MA) is a molecular biological method that investigates genetic factors as a cause of death. Recent advances in genome sequencing technology have enabled forensic scientists to conduct comprehensive genetic testing in addition to gross autopsy for investigating hereditary cardiac diseases that could cause SCD.
Some hereditary cardiac diseases show an autosomal dominant inheritance pattern and are clinically actionable, which means cardiac events in family members may be prevented through identification of at-risk family members and appropriate medical intervention.6 Thus, the diagnosis of hereditary cardiac diseases via MA has 2 results: (1) identification of the cause of death and (2) future health management for relatives of the deceased.2
Several guidelines from Europe, Australia, the USA and Asian countries recommend MA after gross autopsy in young SCD victims and cascade genetic testing of relatives as cardiac event prevention and to show the process of the MA has clinical utility.7–12 Ideally, a postmortem examination including subsequent MA should be performed in all cases of SCD among the young. However, the autopsy rate in Japan is relatively low among developed countries,13 and 1 reason is the complicated autopsy process in Japan. Judicial autopsy for a sudden death victim is performed only if the coroner considers the death as unnatural. Even if the death was not considered as unnatural, psychological resistance to autopsy by the bereaved family is also a barrier to conducting a gross autopsy.14 Additionally, the bereaved family members of SCD victims are usually in a state of great confusion and extreme sorrow, making it more difficult to discuss the need for an autopsy.15–18 Thus, a considerable number of autopsies for SCD cases are likely not performed and the reason for the death remains unrevealed.
Implementation of an autopsy process that includes MA faces many challenges in various contexts: social, cultural, economic, political, legal and physical environments. It is essential that all stakeholders understand the challenges and collaborate to tackle them. However, the details of the challenges in implementing an autopsy process including MA in the context of the autopsy system in Japan remain unclear. This study aimed to ascertain healthcare professionals’ opinions regarding MA in order to clarify these challenges, as well as stakeholders’ opinions surrounding its implementation for young SCD victims, including subsequent preventive intervention for the deceased’s family members.
This study was a qualitative exploratory study that analyzed interviews of healthcare professionals who are expected to be involved in the process of MA and the creation of preventive strategies for victims’ family members. Focus groups (FGs) were utilized to collect data because we wanted to collect expert opinions on topics that were unfamiliar to the participants. The FG is a suitable method for recording opinions through inter-participant discussions.19 We allowed both face-to-face and online FGs, depending on the participants’ preferences.
The MA process involves healthcare professionals from various disciplines.7,8,20,21 To collect these multidisciplinary opinions and organize the opinions from each related specialty, we conducted FGs in 2 steps (Figure). In the first step, members with the same expertise gathered for a discussion. The categories of expertise in the FGs were emergency medicine (group E), forensic medicine (F), cardiology (C), and clinical genetics and counseling (G). In the second step, FGs with 4 members were formed, with a representative from each category.
Flowchart of focus groups (FGs).
As stakeholders in the MA process,7–12 fluent Japanese experts (>5 years’ experience in relevant field) from the following fields were recruited via purposeful and snowball sampling: emergency medicine (Emerg), forensic medicine (Forensic), cardiology (Cardio), or clinical genetics (Genet). The number of people in each area of expertise was set at 3–5. Background characteristics of participants with each expertise were as balanced as possible: age, sex, residential area, and experience in the MA process.
Setting and Data CollectionThe FG sessions were conducted between September and December 2019. The researcher (K.K.) explained the background, purpose, methods, and significance of the study to each of the participants either by email or face-to-face using a written document. After obtaining written consent from each participant, a written interview guide was distributed, instructing them to prepare their opinions prior to the FG.
The FG session were held either face-to-face or through secure online virtual platforms. The face-to-face FG sessions were conducted in a private room; the venue of the online FG sessions depended on the participants’ convenience. Participants were formally instructed to ensure their privacy during the FG sessions. As an introduction to the FG, K.K. briefly explained the purpose, methods, and significance of the study; the definitions of terms and concepts regarding MA and genetic counseling, and the MA process. This was done to even out the participants’ knowledge levels. The FGs were moderated using interview guides designed by the researchers and piloted prior to the FGs (Table 1). The duration of the FG sessions was approximately 1 h.
| Introduction | |
| Overview of the topic | In recent years, it is recommended the molecular autopsy for the young unexpected sudden cardiac death victims in negative autopsy and it might help for at-risk family members. |
| Object | I would like to discuss with all of you for clarifying the challenges of implementation of molecular autopsy process based on sudden cardiac death in children and young adult. |
| Definition | In this study, we defined the meanings of those words: SCD; unexpected, non-traumatic, cardiac etiology (presumed) sudden death MA; postmortem germline genetic testing MA process; not just postmortem genetic testing, including the process of recognition of cardiac arrest, emergency care, genetic counseling, and preventive intervention for family members |
| Questions | |
| Introductory question | Do you feel the importance of exploring genetic causes in case of negative autopsy SCD victims among young adults and children? Please state your reason. |
| Transition question | What do you think about your expertise’s role if you participate in the MA process? |
| Key question | What challenges or problems are there in Japanese clinical settings? |
| Ending question | (After demonstrator summarized the essence of the session) Is this an adequate summary? Is there anything you would like to add? |
MA, molecular autopsy; SCD, sudden cardiac death.
The FG sessions were recorded and analyzed following the methodology of content analysis;22 the transcribed data were open coded and categorized. Prior to the FGs, KK visited and observed clinical practice in all the fields related to MA, such as the emergency room, cardiology center, and dissecting room. All the analytic processes were supervised by MN (PhD, RN, PHN, CGC), an experienced nurse, certified genetic counselor, and researcher in the field of qualitative research.
Ethical ConsiderationsThe Ethics Committee of Kyoto University Graduate School and Faculty of Medicine approved this study protocol, which adhered to the principles of the Declaration of Helsinki (approval number: R2065). All participants received written and verbal information about the aim, significance, and methods of the study. Written consent was then given by them all.
In all, 31 healthcare professionals (21 men, 10 women) participated in this study. The participants were all specialists in their fields: emergency physicians (n=7), forensic physicians (n=6), forensic scientist (n=1), cardiologists specializing in ischemic disease (n=5), cardiologists specializing in cardiac arrhythmia (n=5), medical geneticists (n=3), and certified genetic counselors (n=4). The mean clinical experience in their respective fields was 11.9 years. The length of the FGs was 38–69 min (mean 56.5 min) (Table 2).
| Context of FG | Group number |
Medical profession |
Length of clinical or practice experience, mean and range (years) |
Sex | Length of FG session (min) |
|---|---|---|---|---|---|
| First-step FG sessions | |||||
| Emergency medicine | Emerg 1 | 4 medical doctors | 10.0 [8–13] | 4 male | 38 |
| Emerg 2 | 3 medical doctors | 8.3 [7–10] | 1 male, 2 female | 58 | |
| Forensic science | Forensic 1 | 3 medical doctors | 11.7 [10–13] | 2 male, 1 female | 52 |
| Forensic 2 | 3 medical doctors, 1 medical technologist |
16.8 [12–29] | 4 male | 69 | |
| Cardiology | Cardio 1 | 3 medical doctors | 9.0 [8–13] | 3 male | 53 |
| Cardio 2 | 3 medical doctors | 16.0 [12–22] | 1 male, 2 female | 44 | |
| Cardio 3 | 4 medical doctors | 10.5 [6–14] | 2 male, 2 female | 57 | |
| Medical genetics | Genet 1 | 3 certified genetic counselors | 5.0 [5–5] | 2 male, 1 female | 62 |
| Genet 2 | 2 medical doctors, 2 certified genetic counselors |
17.0 [5–32] | 2 male, 2 female | 58 | |
| Second-step FG sessions | |||||
| Multidiscipline | Multi 1 | 4 medical doctors | 10.3 [5–20] | 3 male, 1 female | 69 |
| Multi 2 | 3 medical doctors, 1 certified genetic counselor |
21.3 [10–32] | 3 male, 1 female | 62 | |
Cardio 1: 3 cardiologists specializing in ischemic disease. Cardio 2: 3 cardiologists specializing in cardiac arrythmia. Cardio 3: 2 cardiologists specializing in ischemic disease and 2 in cardiac arrythmia. FG, focus group.
The participants considered that the MA had 2 clinical values: (1) further discovery of the SCD’s unknown cause, and (2) SCD prevention among victims’ family members.
Regarding the discovery of the SCD’s unknown cause, the participants set value in the MA that could reveal previously unknown causes even after the cremation of the victim if the DNA was preserved. They also regarded MA as a preferable form of autopsy for bereaved family members because it could avoid the necessity for hasty decision-making, could avoid damage to the corpse, which could be a psychological burden, and ease the family’s feelings of guilt.
The participants also set value for MA in the prevention of SCD among the bereaved family members because hereditary cardiac diseases (HCDs) identified via MA are mostly preventable through adequate medical intervention. The narrative data of participants are provided below.
“Parents of the young victims, and also we, are wondering why he/she had to die. We usually recommend an autopsy after obtaining uninformative results using a postmortem CT scan. However, the parents often withdraw that offer because they do not want to hurt their child’s corpse, and the cause of death remains unknown forever. MA can be an alternative to invasive autopsy for those bereaved family members.” (In Emerg 2 session, female, emergency physician)
“The bereaved family members sometimes show a sense of regret because they feel responsibility for the death of SCD victims. They sometimes blame themselves for being unable to notice a sign or the risk of cardiac arrest, even though no one can notice them. If they knew that the cause of death of the victims is in their genes, they would be relieved from their responsibility. However, some people may feel more regret when it turns out to be inherited from them.” (In Emerg 2 session, female, emergency physician E)
“If the first event is SCD, there is no opportunity to identify the genetic information of phenotypic patients other than collecting DNA from the victim. This is a meaningful process for SCD prevention in the family if one heritable cardiovascular disease exists in the pedigree.” (In Genet 1 session, male, certified genetic counselor C)
“To investigate the cause of death and return it to the bereaved family and society is an essential philosophy of forensic science. From this viewpoint, MA is a meaningful method because it not only reveals the unknown cause of death, but also shows a way to protect the bereaved family members from life-threatening events.” (In Forensic 1 session, male, forensic scientist A)
Considerations for Bereaved Family MembersThe participants voiced several concerns about MA: it could detect a HCD that currently has no known effective intervention, whether cure or prevention; it could result in a sense of guilt in the victims’ parents regarding the inheritance of genes with the pathogenic variant; it could cause fear of SCD among other family members; it could obstruct their right to “not to know”; it could force the victims’ family members to wait for a long time due to the turnaround time of genetic testing; the MA process could be confusing for the bereaved family; it could be difficult to set adequate time for genetic counseling; the misperception that MA replaces conventional autopsy; and cost effectiveness.
“Even if a pathogenic variant was identified by MA, the result cannot be utilized for the family members if the disease has no effective intervention for cure or prevention. Such information could only be a burden for the bereaved family members.” (In Emerg 2 session, female, emergency physician F)
“Some family members might think that they would die, too.” (In Emerg 2 session, male, emergency physician E)
“The involvement of too many professionals in the process of bereavement can cause confusion in the family.” (In Genet 2 session, female, certified genetic counselor E)
“Genetic counseling is generally recommended for family members at risk of heritable disease. However, in the process of MA, it may be premature to offer genetic counseling immediately after bereavement.” (In Genet 2 session, female, certified genetic counselor E)
Challenges in the MA Delivery SystemVarious challenges in the MA process, from the occurrence of SCD to the return of genetic information and introduction of preventive interventions to the bereaved family members, were identified (Table 3).
| Process | Categories |
|---|---|
| Obtaining consent for the MA | Low awareness of the MA among healthcare professionals and the general public |
| Difficulty in establishing trust with bereaved families in a short period of time | |
| Lack of time to explain the MA | |
| Lack of knowledge of handling the samples: collecting, storing, and ordering | |
| Lack of personnel to explain the MA | |
| Regional and institutional differences in ability to describe MA | |
| Slight timing for blood sample collection | |
| Cause of death investigation | Low awareness in forensic scientists of usefulness of MA in further investigation of unexplained sudden death |
| Lack of knowledge about the genetic testing process | |
| Interpretation of postmortem genetic test results | |
| Complexity of the types of autopsies and the legal basis for them | |
| Regional and institutional differences in ability to perform and interpret the results of the MA | |
| Cannot perform the analysis at own institution | |
| Lack of budget for postmortem examinations | |
| Postmortem examinations are not covered by insurance | |
| Quality control of the samples | |
| Cost of storage of samples | |
| Difficulty in selection of genes to investigate | |
| Cautiousness about genetic testing | |
| Low autopsy rate | |
| Disclosing results | Disconnection of the relationship between tertiary hospital and the bereaved family after the death of victim |
| Divergent interpretations of the laws about disclosure of autopsy results | |
| Tenuous relationship between forensic scientists and clinicians | |
| No genetic counseling before the MA | |
| Secondary findings from comprehensive genetic analysis | |
| Preventive intervention | Difficulties in encouraging asymptomatic carriers to visit the hospital for preventive care |
| Hesitation about cascade screening of family members | |
| Invasive nature of preventive treatment | |
| Preventive interventions are not covered by insurance |
MA, molecular autopsy.
First of all, low awareness about MA among healthcare professionals is a fundamental challenge for the MA process. No process will start if stakeholders do not recognize its usefulness and availability. In the process of obtaining consent, there are challenges of what and how much information should be provided to the bereaved family in a limited time. In the process of cause of death investigations, there is the challenge of integrating MA results into existing autopsy results and other postmortem examinations. Integration of multiple autopsy results was raised as a common issue in the general investigation of cause of death. In the process of disclosing the results, issues related to the relationship and communication with family members were mentioned. In the process of preventive intervention, difficulties in encouraging family members to take part in the preventive process included cascade screening, invasive nature of preventive interventions, and issue of health insurance. The issues of low awareness, lack of knowledge and personnel, gaps in activity by regions or facilities, and budget overlay each step in MA delivery.
“We have to store the samples before cremation; however, we don’t have enough time to provide information to the family, obtain consent for the MA, and collect blood from the victim. We do not have enough time to complete the procedure while treating critical patients one after another.” (In Emerg 2 session, female, emergency physician E)
“The cause of death investigation is of high public interest and is usually borne by public funds, while prevention of SCDs in bereaved family members is of private interest. Therefore, it is a complicated topic whether the cost should be covered by the public budget or private budget of the family.” (In Forensic 1 session, male, forensic scientist C)
“Forensic scientists are legally prohibited from discussing autopsy results with the bereaved family if there is a possibility of litigation.” (In Forensic 2 session, male, forensic scientist D)
“I guess almost all cardiologists in the general hospitals don’t have enough knowledge about autopsies and clinical genetics; the way of taking and keeping samples for MAs or where we have to send those samples. Then, we cannot tell the bereaved family about the MA.” (In Cardio 2 session, male, cardiologist E)
“It makes sense if the main purpose of the MA is to investigate the cause of death; however, if it is to prevent cardiac events among family members, we should discuss whose right will have to be prioritized.” (In Genet 2 session, female, certified genetic counselor E)
The results of the FGs featuring stakeholders of the MA process revealed 2 values, some concerns, and various challenges in the implementation of MA related to SCD in clinical practice.
The clinical values of MA found by the participants were as expected: (1) to investigate the cause of death, and (2) to prevent SCDs in the remaining family members. The primary value of MA varied according to each participant’s specialty. Forensic scientists were focused on revealing the cause of death, and had little concern about whether the family members agreed with genetic testing. On the other hand, geneticists and cardiologists mainly focused on prevention among the victims’ family members. They believed that consent from the victims’ family members and their decision on whether they wanted to know the results of the MA were important, because it could reveal the risk status of family members as well as identifying the cause of SCD in the victim. These results indicated that the consent process should take the 2 values of MA into account.
The process of obtaining consent by forensic scientists must include disclosure to the victims’ families that the results of the MA may reveal facts about the health of the family members themselves. Thus, a 2-step consent process would be suitable: (1) determining whether the family members consent to the MA of the victim, and 2) determining whether the family members (and if yes, which ones) want to know the results of the MA. This process is particularly important in preparing results that detect pathogenic variants in genes related to cardiovascular disease without effective treatment and/or prevention strategies. It may be necessary to consider selecting genes (i.e., actionable genes6) for disclosure instead of disclosing the results for all target genes.
The concerns about MA also extended to the psychological state of the bereaved family members. The participants mentioned that the results of a MA may cause 2 types of guilt among family members. First, they could regret the fact that if they had known that the victim carried the pathogenic variant in a SCD-related gene, the death could have been avoided. Second, they, especially the parents of the victim, could blame themselves for possibly passing the pathogenic variant to their child. This sense of guilt could be prevented or relieved through genetic counseling. In fact, several previous studies in the field of emergency medicine and cardiology report that genetic counselors play an important role in the process of grief and loss in family members, adjustment to the inheritance risk in the family, and lifestyle modification.23–26 Genetic healthcare professionals such as clinical geneticists or certified genetic counselors should be involved in the MA process in order to promote correct understanding of and adaptation to genetic phenomena.
Various ethical, legal, and social issues were discussed during the FGs. In addition to the themes that were revealed in previous research, the present study’s findings emphasized the ethical and social issues in obtaining the bereaved family’s consent. First, it is difficult to determine the appropriate time for obtaining consent for a MA. Second, Japanese people usually reject autopsies because of cultural aspects that corpse their own wills, standpoints, and wishes.27 In addition to the general population, healthcare professionals sometimes tend to have a passive attitude toward MA, which can prevent the victim’s family members from obtaining adequate information about MA, and thus, giving their consent for the same. Even if MA is clinically feasible, gross autopsies remain important. Forensic scientists showed concern that the widespread implementation of MA could further reduce the understanding of the importance of gross autopsies. Thus, it is essential to implement MA as a further investigation strategy for cases in which conventional autopsy delivers a negative finding.
With respect to legal issues, the ambiguity of regulations regarding the handling of forensic autopsy results is a barrier to sharing the results with fellow clinicians as well as bereaved family members. Article 47 of the Code of Criminal Procedure states: “No document relating to a trial may be made public prior to the commencement of the trial; provided however, that this does not apply when it is necessary for the public interest or other reasons, and when it is deemed to be appropriate.” Legal judgment on sharing or disclosing the results is often difficult for forensic scientists. More recently, in April 2020, the “Basic law on the acceleration of probes into the cause of death and identification” was administered. This law claims it is the responsibility of national and local governments to share the autopsy results with healthcare professionals for clinical utilization of the results. Responsibility to facilitate adequate disclosure of the results to the bereaved family was also claimed in the law. These legal statements will encourage healthcare professionals, including cardiologists and geneticists, to be involved in the autopsy process. We therefore expect MA and subsequent prevention strategies for relatives of the victims to be implemented on a legal basis.
Generally, processes specific to each specialty are well established: the molecular analysis of blood samples, disclosure of the results of genetic testing, genetic counseling, and preventive intervention for at-risk populations. However, the process of connecting these specialties has yet to be developed. Thus, the establishment of interdisciplinary teams (i.e., forensic, pathology, genetics, and cardiology), as well as their persistence and cooperation, is essential to the development of a thorough MA process.
Clinical ImplicationsMany challenges were comprehensively identified in this study and although all were crucial in the MA process, some need to be tackled preferentially.
First, cardiologists and geneticists should be actively involved in the process of cause of death investigation in the case of young unexplained sudden death. SCD due to hereditary arrhythmia is not identified by thorough gross autopsy. Retrospective review of previous ECG (if available) and genetic testing should be considered as an additional investigation strategy in such cases. However, few cardiologists or geneticists were currently involved in the autopsy process. Challenges in the MA process include adequate selection of targeted genes and interpretation of the result, which can be resolved by the multidisciplinary approach.10,12
Second, clinical utility of MA for prevention of SCD among remaining family members should be recognized, especially by forensic scientists and cardiologists. MA is not only a means of investigation for cause of death, but also the beginning of preventive medicine. Awareness of MA’s clinical value in preventive medicine would reduce cautiousness about genetic testing, difficulties in outreach to family members, and the hesitation for cascade screening. At the same time, robust evidence about preventive strategies for asymptomatic carriers of HCD should be established.
Study LimitationFinally, we have to mention a possible bias of this study. Although the participants were sampled considering their age, sex, field distribution, and involvement in MA, those who gave their consent to participate in this study may have been more positive about MA. It should be noted that the stakeholders held those opinions at that time, before several guidelines and the “Basic law on the acceleration of probes into the cause of death and identification” were released in April 2020.
This study explored the expectations and challenges regarding the MA process. The 2 values of MA and the complex characteristics of genetic information could be a source of concern and confusion among both healthcare professionals and bereaved family members. Thus, increasing awareness about the MA process among healthcare professionals is essential for connecting all areas of expertise related to MA in Japan and elsewhere.
The authors thank all the healthcare professionals who participated in the FG sessions. We also thank Seiko Ohno, Department of Bioscience and Genetics at the National Cerebral and Cardiovascular Center, Hirokazu Kotani, Department of Forensic Medicine and Sciences at Mie University Graduate School of Medicine, Takuma Yamamoto, Department of Legal Medicine at Hyogo College of Medicine, Taku Iwami, Department of Preventive Services at Kyoto University School of Public Health, and Yohei Okada, Department of Preventive Services at Kyoto University School of Public Health and Department of Primary care and Emergency Medicine at the Graduate School of Medicine Kyoto University, for their contributions to the fields related to MA and sampling participants. Support for this study was provided by the Kyoto University School of Public Health.
The authors declare no competing interests.
The Ethics Committee of Kyoto University Graduate School and Faculty of Medicine approved this study, which adhered to the principles of the Declaration of Helsinki (approval number: R2065).
The deidentified narrative data will be shared on a request basis immediately following publication to March 2029. The data will be shared as Excel files via email.
