Secondary findings from next generation sequencing: Psychological and ethical issues. Family and patient perspectives.

Access to active search for actionable secondary findings (SF) in diagnostic practice is a major psychological and ethical issue for genomic medicine. In this study, we analyzed the preferences of patients and their families regarding SF and identified the reporting procedures necessary for informed consent. We interviewed parents of patients with undiagnosed rare diseases potentially eligible for exome sequencing and patients affected by the diseases listed in the ACMG recommendations. Four focus groups (FG) were formed: parents of patients with undiagnosed rare diseases (FG1, n = 5); patients with hereditary cancers (FG2, n = 10); patients with hereditary cardiac conditions (FG3, n = 3); and patients with metabolic diseases (FG4, n = 3). Psychologists presented three broad topics for discussion: 1. Favorable or not to SF access, 2. Reporting procedures, 3. Equity of access. Discussions were recorded and analyzed using simplified Grounded Theory. Overall, 8 participants declared being favorable to SF because of the medical benefit (mainly FG1); 11 were unfavorable because of the psychological consequences (mainly FG2, FG3, FG4); 2 were ambivalent. The possibility of looking for SF in minors was debated. The 4 key information-based issues for participants ranked as follows: explanation of SF issues, autonomy of choice, importance of a reflection period, and quality of interactions between patients and professionals. Examining equity of access to SF led to philosophical discussions on quality of life. In conclusion, individual experience and life context (circumstances) were decisive in participants' expectations and fears regarding access to SF. Additional longitudinal studies based on actual SF disclosure announcements are needed to establish future guidelines.

Secondary findings from whole-exome/genome sequencing evaluating stakeholder perspectives. A review of the literature.

With the development of next generation sequencing, beyond identifying the cause of manifestations that justified prescription of the test, other information with potential interest for patients and their families, defined as secondary findings (SF), can be provided once patients have given informed consent, in particular when therapeutic and preventive options are available. The disclosure of such findings has caused much debate. The aim of this work was to summarize all opinion-based studies focusing on SF, so as to shed light on the concerns that this question generate. A review of the literature was performed, focusing on all PubMed articles reporting qualitative, quantitative or mixed studies that interviewed healthcare providers, participants, or society regarding this subject. The methodology was carefully analysed, in particular whether or not studies made the distinction between actionable and non-actionable SF, in a clinical or research context. From 2010 to 2016, 39 articles were compiled. A total of 14,868 people were interviewed (1259 participants, 6104 healthcare providers, 7505 representatives of society). When actionable and non-actionable SF were distinguished (20 articles), 92% of respondents were keen to have results regarding actionable SF (participants: 88%, healthcare providers: 86%, society: 97%), against 70% (participants: 83%, healthcare providers: 62%, society: 73%) for non-actionable SF. These percentages were slightly lower in the specific situation of children probands. For respondents, the notion of the «patient's choice¼ is crucial. For healthcare providers, the importance of defining policies for SF among diagnostic lab, learning societies and/or countries is outlined, in particular regarding the content and extension of the list of actionable genes to propose, the modalities of information, and the access to information about adult-onset diseases in minors. However, the existing literature should be taken with caution, since most articles lack a clear definition of SF and actionability, and referred to hypothetical scenarios with limited information to respondents. Studies conducted by multidisciplinary teams involving patients with access to results are sadly lacking, in particular in the medium term after the results have been given. Such studies would feed the debate and make it possible to measure the impact of such findings and their benefit-risk ratio.

On the difficulty to communicate with fMRI-based protocols used to identify covert awareness.

Assessment of awareness in patients with disorders of consciousness such as patients in a vegetative state (unresponsive wakefulness syndrome, UWS) and patients in a minimally conscious state (MCS) remains difficult, with a high rate of misdiagnosis (around 40%). While patients with UWS have no awareness, patients with MCS have partial preservation of conscious awareness. To improve the assessment of awareness in these patients, recent functional neuroimaging protocols have been developed. However, does the complexity of realizing and interpreting these functional magnetic resonance imaging (fMRI) investigation protocols, which are currently carried out by only a few specialist teams, permit generalizable use in clinical routine? In this study, 32 healthy volunteers, by definition perfectly conscious and able to efficiently communicate, performed the protocol proposed by Monti et al. in 2010. Four methods (comprising the method proposed by Monti et al., a mean squared error-based method, a correlation-based method, and a support vector machine-based method) were tested for correctly and accurately interpreting the communication task. Firstly, the different instructions for the localizer and the communication tasks had no effect on activations. Secondly, 25% of participants (8/32) did not provide the expected patterns of activations during fMRI tasks (four for each imagery task). However, this did not necessarily prevent the classification methods from correctly guessing the answers during the communication task. Conversely, these classification methods may fail to detect the correct answers even though participants activated the expected brain areas. None of the four methods produced 100% correct detection during the communication phases. The correlation-based method obtained the best results with an error rate of 4.2%. The results of this study demonstrate that fMRI-based communication paradigms may not be robust enough to reliably detect awareness in all aware patients. There is still a need to develop new statistical and analytical methods before considering their generalization in clinical routine.

Substitute or complement? Defining the relative place of EEG and fMRI in the detection of voluntary brain reactions.

To improve the assessment of awareness in patients with disorders of consciousness, recent protocols using functional Magnetic Resonance Imaging (fMRI) have been developed, and led some specialized coma centers to use this method on a routine basis. Recently, promising results have also been observed with electroencephalography (EEG), a less expensive and widely available technique. However, since the spatiotemporal nature of the recorded signal differs between both EEG and fMRI, the question of whether one method could substitute or should complement the other method is a matter of debate. In this study, we compared the neural processes of two well-known EEG and fMRI mental imagery protocols to define the relative place of each method in the assessment of awareness. A group of 20 healthy volunteers performed both EEG and fMRI command-following and communication tasks. Distinct command following was found with both EEG and fMRI for five subjects, only with fMRI for 12 subjects, and only with EEG for one subject. In the communication task, neither EEG nor fMRI alone gave satisfactory results and no reliable communication could be established in approximately 1/3rd of the participants. If fMRI showed the best performance to detect volitional reactions in mental imagery tasks, our results provide evidence that the use of EEG must not be underestimated since a better detection was found with this method for at least one subject. More than being used as a substitute, EEG should complement fMRI to improve the detection of sign of awareness, and to reduce the risks of misjudgments.