The deep brain stimulation (DBS) in early-stage Parkinson’s disease (PD) pilot trial began more than a decade ago and remains the only investigation of DBS in mildly symptomatic patients. Patients completed therapeutic washouts biannually for two years, outpatient assessments through five years, and a longitudinal washout assessment after 11 years. Here, the patient experience of participating in the early DBS pilot trial is described. Semi-structured interviews were audio-recorded and transcribed. Transcripts were coded, analyzed using an iterative inductive-deductive approach, and used to develop a conceptual framework. Ten participants , n = 4 early DBS + ODT) were interviewed. Motivations for participation included benefit to future PD patients and potential personal benefit, while hesitations included risk of surgical complications. While early ODT patients who received standard-of-care DBS described significant changes in their functional capacities after surgery, early DBS patients described a maintenance of quality of life that made PD less impactful over an extended period. Patients expressed high satisfaction with trial participation and early DBS. This study suggests that the PD experience with early DBS may notably differ from standard-of-care DBS. The FDA has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016). Deep brain stimulation (DBS) is an adjunctive treatment currently offered to patients with mid-to-advanced stage Parkinson’s disease (PD) that provides significant improvement in motor symptoms, reduces medication burden, and enhances quality of life ,3,4,5,6.The robust benefits of DBS in later stages of PD ,3,4,5,6,In addition to safety and efficacy, which will be evaluated in a future pivotal clinical trial (IDE#G050016), patient experience is a key consideration in determining the viability of early DBS therapy. Unlike patients who receive DBS as a last-resort treatment per standard care, patients from the early-stage PD pilot trial offer the unique perspective of receiving the therapy while only mildly symptomatic. Therefore, to understand the patient perspective of PD progression after receiving early DBS, we interviewed 10 patients 11 years after enrolling in the DBS in early-stage PD pilot trial. Additionally, this cohort provides insight into the patient experience of a novel trial design that involves repeated week-long therapeutic washouts designed to capture PD symptoms in the untreated state. This study describes the long-term patient experience of participating in the only trial of DBS in early-stage PD.The DBS in early-stage PD pilot was a prospective, randomized, controlled, single blind clinical trial . The trial enrolled patients 50–75 years old with very early-stage PD  . After pAll patients previously enrolled in the early DBS pilot trial  who completed the 5-year outpatient follow-up study were approached by phone to participate in this sub-study (IRB191728). This interview study includes 9 out of the 12 patients who completed the 11-year follow-up study and 1 patient who declined to participate in the 11-year follow-up study but agreed to be interviewed. Reasons for non-enrollment included inability to coordinate with patient’s caregiver (n = 1), decision not to participate (n = 1), and loss to follow-up n = 1; . All patAn interview guide was developed with input from Vanderbilt University Qualitative Research Core (VU-QRC) personnel . Due to the unique nature of the patient group, the interview guide was not pilot tested. Interview questions covered topics of the impact of the disease on patients’ lifestyle over time, patients’ expectations and satisfaction with treatment, patients’ judgements of practicability of the early DBS treatment, and patients’ washout experiences.Telephone interviews were conducted by a VU-QRC coordinator  within 1.5 years of completing the 11-year follow-up study visit. The interviewer had no prior relationship with study participants. Mean interview duration was 40 min (23 min–64 min), and three participant interviews had caregivers present. Audio-recorded interviews were stored on an encrypted drive on a secured server until transcribed by the IRB-approved service rev.com.The Parkinson’s Disease Quality of Life Questionnaire 39 (PDQ-39) was administered at baseline for all participants and at 11 years for the 9 out of 10 participants who completed the 11-year study visit.Qualitative data coding and analysis was managed by the VU-QRC, led by a PhD-level psychologist (D.S.). A hierarchical coding system was developed and refined using the interview guide and a preliminary review of the transcripts. Top-level categories in the coding system: (1) symptoms, (2) quality of life, (3) emotions, (4) washout, (5) DBS experiences, (6) change over time, (7) study experience, and (8) PD experience. Each category had 4–16 subcategories, some of which included three additional levels of hierarchical division. Definitions and rules were written for the use of coding categories.Two trained qualitative coders  first established reliability in using the coding system on two transcripts, reconciling any discrepancies, then independently coded the remaining transcripts. Each speaking turn was treated as a separate quote, and each quote was given 0–13 codes. Transcripts were combined and sorted by code. The transcripts, quotations, and codes were managed using Microsoft Excel 2016 and SPSS version 27.0.Mean patient age at interview was 72.4 ± 6.3 years (64.9–85.0) and mean PD medication and illness duration was 14.4 ± 1.9 years Some described early DBS as an additional tool to combat PD:Knowing what DBS was intended to do, it just concerned me that it was not made available to people who were diagnosed with Parkinson’s and otherwise healthy, and if it could be an extra tool to help combat the disease or make things easier, then why not make it available to people with early [stage PD]. I was quite hopeful during this selection process that I would get selected and [was] glad I did. Motivation for others stemmed from a desire to help future PD patients:I regarded it as an altruistic move on my part, to take part in the study. I did not see... how I was going to benefit from it at all… But it would provide useful information for the curing of Parkinson’s. Hesitance to accept the risks of brain surgery while still functioning adequately with PD emerged as reservation about study enrollment:He was functioning just fine, at that time. He continued to drive, he continued to do his activities of daily living independently... one of the doctors said that they had expected that they wouldn’t have enough volunteers because who would want to have brain surgery when they weren’t having any problems? Because that can be a scary process, regardless of your diagnosis. The surgery itself caused hesitation for some but not for all:The thought of having brain surgery while still conscious was not very appealing to me. I didn’t hesitate to get the operation. … I was not afraid of it... I think some people would be bothered by the idea of brain surgery, but it didn’t bother me. Uncertainty surrounding PD also caused hesitation:Well, with my wife, there were concerns in the family as to whether or not I was doing the right thing. Again, back then, not a lot known about Parkinson’s. Patients discussed the thoughtful nature of the expanded, three-part informed consent process led by a medical ethicist :It’s not something that once you sign a piece of paper, they say, “Well, come on. We’ll do it.” With the study, it’s a very thoughtful process. One patient expressed determination to receive DBS that did not waver during the consent process:Of course, once I understood the program, I was very anxious to get the device, be proactive about it... I remember saying [to the medical ethicist], “I understand that there’s a 5% chance of a brain bleed during the operation, but I also understand there’s a 30% chance of early-stage dementia with Parkinson’s. What would you do? It’s an easy decision for me.” When considering whether they would recommend participation in a similar study to others with PD, a caregiver noted the significant time, emotional commitment, and perseverance required:If I told them to consider it, I hope they would be in it for the long haul, because trust me, five years is a long time going every six months. If they’re going to go, I would hope that they would stick it out and finish it, because that’s the only way that, I guess, we got this far. I mean, we’ve stuck it out not only spiritually, but mentally... we didn’t miss a time. And yes, it was stressful, because we knew six months from that time, we would be going back into the hospital. For one, the week-long washouts and recovery periods interfered with work:I would not feel what I considered back to where I had been prior to the stay for maybe a week. And that’s really what caused me to step back from my position at work at that time. Because I was out eight days and it’d take me about a week to get straightened out. So every six months, I was two weeks out. And when you’re on production quotas and recruiting quotas and you get so far behind, then it’s just a stressful situation trying to keep up. Camaraderie and shared experience emerged as prominent and enjoyable aspects of study participation:It was really, to be honest, the first time or the second time I was there, I found it very comforting to have other guys around with similar problems. My wife and my family were very sympathetic, but they couldn’t really understand what I was going through. These guys could. So going in and staying for eight days at a time off medication was a challenge. But it was interesting to have other folks there to do that with… Yeah, that’s been a lifelong impact. … I expect to be connected to those guys. As long as you struggle with this thing. Patients expressed a sense of connection to the PD community and its resources:The best thing that happened to me recently was meeting [study neurologist] and getting into the program. That gives me people to associate with who are positive and enthusiastic and it gives me some directions. It’s a shame that everyone who has Parkinson’s can’t be connected with the people that have the best advice like I have. Despite challenges with the washout periods (see Washout Experience), patients largely expressed satisfaction with trial participation. Satisfaction was discussed in terms of feeling taken care of, potential benefit to others, and empowerment:He was taken very good care of and he always feels very safe and that eventually, somehow, this is going to help. It’s just been neat to have opportunities to feel like you have a framework in which to fight back against this disease. An early DBS patient noted subsidization of surgery costs as part of being in the clinical trial:I would say if that’s the only way you can get the device during the early stages, I’d say do it for sure… I would recommend that people get deep brain stimulation early, by hook or by crook. I realize that … I got [the] operation at least, for free, so I certainly appreciate that. That was worth the investment of my time. Randomization into the control group was regarded as a disappointment:There were some very disappointed patients... some were very upset that their number was not chosen as one of the surgery patients. I did not receive it [DBS], originally. … It would have been nice if I’d had it sooner, but in reflection, I guess it’s kind of worked out just about right. They advanced… the electrodes going into the skull... I got one of the later models. The washout involved stopping the use of PD medications and, if applicable, turning off DBS devices for seven days to assess physical and cognitive symptoms of PD in the absence of treatment. Washouts were completed at baseline and every six months during the pilot trial (early-stage PD) and attempted again at the eleven-year study visit [I hoped] that I would not become more dependent on others, that I would still be capable of dealing so much. I did not know... how I dreamt of it. I just assumed it [DBS] would do no harm. Common coping strategies for living with PD included information seeking, establishing a medication routine to make dosage-related symptomatic variability more predictable, and finding tricks to manage individual symptoms . Social Early DBS patients utilized similar coping strategies, as well as additional methods particular to their treatment. While they employed similar medication management techniques as those randomized to ODT, some expressed relief at the constancy of DBS:The problem I have with [medications] is remembering to take them and trying to remember if I did take a dose and remembering to take the next dose. Fortunately, with the DBS, once it’s on, it’s on. Adjusting DBS settings provided new opportunities to control symptoms, though this also required a learning period for patients:Our goal when we went to [doctor], was to get him to enable [patient] to speak more clearly. That was my goal that I stated. That if he could just speak more clearly and they did indeed see that an adjustment could be made for that purpose. And he does speak more clearly now. .At one point, the settings might have been a little bit too high. So it just seemed to intensify my movements. Dyskinesia… I believe at one point, they decided to move from one set of leads down to another in their fine-tuning. I think that helped a lot. Again, it’s a learning process for the patient and the doctors. .As PD progressed over the 11-year period, patients experienced a range of symptom severity and quality of life outcomes . Those wSimilar to standard of care DBS patients, one early DBS patient noticed DBS-related alleviation of specific symptoms, such as tremor and stiffness:Well, it seemed to help a lot with my tremors in the hand and the tenseness, stiffness in my hands and feet and shoulders. That was one thing that just went away. That was no longer a huge event. So that was the biggest thing. More often, however, early DBS patients described minimal noticeable impact in the early months of their DBS:He didn’t feel different than when he didn’t have it, other than his tremor was ended. Well, I remember going to [the study neurologist] … after surgery and feeling that I was disappointed that I could see no improvements in 30 days... I’m only saying that because the light bulb just went on. I totally understand now. I get it, what’s going on. I went in one day and said, “I understand how my brain is working to support the DBS.”... I expected it to be like turning it on and everything will be super. Instead, DBS, it didn’t work. It was a step forward success. It wasn’t a great success. It was another tool that we used to move forward. .Instead, the impact of early DBS was discussed in terms of prevention of major quality of life changes due to PD:Since I had the DBS, everything’s going kind of smoothly. I’m anticipating it getting worse, and quite frankly, I’m at a point it’s starting to slow me down and I’m feeling the effects of Parkinson’s. But up until recently, I was really unaware every day that I had Parkinson’s… It helped me in my attitude. It gave me a lot of confidence because I knew that I had an extra gun in my pocket. So far, [PD has] not affected me very much. I still work full time as a lawyer. I still play golf, a lot. It’s not affected much about my everyday life. It’s a little more difficult to put on my pants, for example, because of balance problems, but in general, have not been affected very much. The inability to identify specific ways DBS was helping emerged as a theme among early DBS patients:It still prevents that tremor in the right hand. I don’t know that it’s helping me in any other way, because it’s hard to say. Because if it is, it’s been doing it for a long time and it’s not something that I notice any longer. I have always felt it probably mitigated some symptoms that he might have if he did not have the DBS, but again that’s nebulous because we don’t know what those would be. We never turn [the DBS] off. However, the washout experience revealed symptoms that were normally masked by DBS and medication:When I was off the device… I could tell that my coordination was substantially compromised. But with the medication and on the device, I didn’t have any particular trouble whatsoever, and most people would not know that I have Parkinson’s disease. Balance, handwriting, speech, constipation, drooling, freezing, and cognition were symptoms that early DBS patients wished their DBS would treat better.Standard of care DBS patients expressed recognition that DBS was not a cure-all and felt satisfied with their treatment despite continuing to struggle with symptoms .Similarly, all early DBS patients (4/4) interviewed expressed satisfaction with receiving early DBS and felt comfortable with the timing of the treatment:It was the best thing that I had ever done. A very positive thing for me. Glad I started early on, would not want to have done it any other way. I know it’s not a cure-all, but I’m glad I got it. To have waited till I got really bad with no hope that there would be no turning back any progression. I would not have liked being put in that situation… I don’t see any negativity with having DBS in my sense at an early stage. It was early in the diagnosis, but it was not early in my age, I was 74 years old and—I believe that was okay… I appreciate it today, the effect from that. Multiple patients felt satisfied because they believed that early DBS slowed their disease progression:Medication that’s available now has not been shown, I believe in any way to slow or stop progression. That’s why the study was done for early [DBS] to see what impact it does possibly have on slowing or stopping progression. In my case, I would have to say it does. But that’s me. In my unique Parkinson’s situation, I believe it has slowed. It’s been 16 years [since joining the study] and until recently, you literally couldn’t tell I had Parkinson’s... I told [study neurologist] the other day … “I probably wouldn’t be here today,” if I hadn’t had all this exchange with him and the team, I probably would have passed away, I think. All early DBS patients (4/4) said they would recommend early DBS treatment to others:I’d tell them to not hesitate, to do [early DBS] for sure. DBS I see not having any kind of a negative factor in any of those situations. I would encourage it greatly… I would encourage anyone that had a noticeable impact in their life due to Parkinson’s, a confirmed diagnosis regardless of whether or not medication was tolerable or they thought it was making a good impact… knowing that medication is time-based, it’s not constant, and Parkinson’s is a progressive disease. This is the first qualitative study evaluating patients who received DBS in very early-stage Parkinson’s disease. In addition to patients who received early DBS, patients randomized to optimal drug therapy also reflected on their experience participating in the DBS in early-stage PD clinical trial. This study not only provides insight into the patient experience of early DBS over 11 years but is also the only qualitative study to examine the long-term experience with DBS alongside patients randomized to a medication control group.Two prevailing motivations for enrollment in the early DBS trial arose in this study: (1) desire to help future PD patients by participating in research and (2) potential benefits of early DBS . Prior studies investigating whether standard-of-care DBS patients would have preferred earlier DBS similarly cited slowing progression and regaining freedoms sooner as motivators, with the additional motivation of eliminating medication side effects earlier . In contMajor hesitations for enrollment in the early DBS trial related to surgery: risk of peri-operative adverse events and receiving surgery while awake. Fear of adverse events is also cited as the major concern for those considering standard-of-care DBS, although the extent of this fear differs among patients ,29. ThisPatients in this study noted the enhanced informed consent process made them feel educated about participating in the clinical trial , which mThe use of repeated, week-long therapeutic washouts was a trial design feature that permitted evaluation of the underlying symptom progression of PD and ultimately led to Class II evidence that early DBS slows the progression of rest tremor . All patPatients randomized to early ODT in the trial but who later received standard-of-care DBS articulated significant improvement in symptoms following DBS implementation. This is consistent with prior reports, where the post-DBS period for standard-of-care patients is often characterized by dramatic improvement in symptoms and quality of life that patients describe as “miraculous,” “feeling reborn,” or a “new chapter in life” ,33,34. SIn contrast, early DBS patients did not describe immediate, impactful improvement to specific symptoms, aside from one patient whose tremor was eliminated. Instead, early DBS patients spoke of the stability of their lives despite living with PD, commenting that for many years after DBS, they were not greatly affected by their PD or were even “unaware” on a daily basis that they had PD. Unlike the standard-of-care DBS patients in this study as well as in prior reports ,33,34, eMore than ten years after receiving the therapy, all early DBS patients expressed satisfaction with receiving DBS, felt comfortable with its timing, and would recommend it to others. This mirrors high satisfaction rates seen with standard-of-care DBS patients ,35,36, aNearly all participants interviewed (9/10) also completed the PDQ-39 at baseline and 11-years. Interview responses related to quality of life for many participants echoed the 11-year change in PDQ-39, with qualitative descriptions offering a complimentary perspective on factors influencing quality of life beyond the single PDQ-39 summary index score. Three participants had PDQ-39 scores at the 11-year visit that were better than when they enrolled in the trial as very early-stage PD patients. All three had received DBS , and this finding is consistent with quality of life improvements after DBS when it is applied in more advanced-stage PD patients . NotablyResults from this study should be interpreted with caution due to its small sample size of only ten patients . Experiences of patients from the pilot trial who were not interviewed, either due to loss to follow up (n = 3), disability (n = 2), death (n = 12), inability to coordinate with caregiver (n = 1), or declination (n = 1), may differ from that of those in this study. Although the sample size is too small for generalization, describing these patient experiences is important, because this is the only existing cohort that has received very early-stage DBS therapy. Results from this small study are hypothesis-generating, and additional research in a larger cohort of PD patients is needed to confirm the importance of the relationships presented in our conceptual framework. Finally, recall bias should be considered since interviews asked patients to remember over an 11-year time frame.This study describes the patient experience of participating in the only clinical trial of DBS in early-stage PD conducted to date. Participants were motivated to enroll in the pilot trial by desire to help future PD patients and the potential to benefit from early DBS therapy, although some hesitated due to the risk of surgical adverse events. Patients expressed satisfaction with their participation, and those who received early DBS were satisfied with their treatment. This study suggests that the experience of early DBS differs substantially from that of standard-of-care DBS due to the difference in the disease experience at the time when the treatment is applied, with early DBS being described as maintaining, rather than drastically altering, quality of life. More investigation is needed to understand the patient experience after receiving early DBS, and the FDA has approved a prospective, randomized, double-blind, pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016).


Existing public health surveillance systems that rely on predefined symptom categories, or syndromes, are effective at monitoring known illnesses, but there is a critical need for innovation in “presyndromic” surveillance that detects biothreats with rare or previously unseen symptomology. We introduce a data-driven, automated machine learning approach for presyndromic surveillance that learns newly emerging syndromes from free-text emergency department chief complaints, identifies localized case clusters among subpopulations, and incorporates practitioner feedback to automatically distinguish between relevant and irrelevant clusters, thus providing personalized, actionable decision support. Blinded evaluations by New York City’s Department of Health and Mental Hygiene demonstrate that our approach identifies more events of public health interest and achieves a lower false-positive rate compared to a state-of-the-art baseline. Machine learning methods enable a new type of public health surveillance that acts as a “safety net” for public health. To offer a rapid, targeted, and effective response to emerging biothreats, public health officials must be able to detect a huge variety of emerging events. Recent, high-profile events highlight the diversity of situations that can affect public health: In February 2020, 50+ residents of a nursing home in Kirkland, Washington were part of one of the first coronavirus disease 2019 (COVID-19) outbreaks in the United States; in October 2019, 100+ people contracted Legionnaires’ disease and Pontiac fever from hot tub displays at the North Carolina state fair; and in March 2018, 90+ people presented to emergency departments in five states with unexplained bleeding that was eventually traced to the use of synthetic marijuana laced with brodifacoum, or rat poison.While existing, widely used disease surveillance systems such as the Centers for Disease Control and Prevention’s National Syndromic Surveillance Program have proven to be effective in detecting outbreaks of known illnesses, or those with common symptomology , these systems are not optimized for early detection of rare events or novel (previously unseen) biothreats. Syndromic surveillance systems typically monitor emergency department (ED) chief complaint data: free-text symptom data reported by each ED patient, recorded by a triage nurse, and sent to local public health organizations from hospitals in their jurisdiction. Chief complaints are typically short free-text strings, for example, “headache and pain in rt arm” or “cough and nasal congestion × 2 days.” These data are mapped to syndromes, like respiratory, fever, and gastrointestinal illness, and from there, spatial cluster detection methods, such as spatial scan statistics . MUSES offers three notable methodological advances:• MUSES eliminates the need for predefined syndromes by learning syndrome categories, including those that characterize rare or novel health threats and occur over a small number of cases, directly from free-text ED data.• MUSES identifies localized case clusters through multidimensional spatial scan statistics, enabling detection of emerging biothreats that may be isolated to a certain hospital or spatial region or to a certain demographic group of patients.• MUSES uses a practitioner in the loop approach to incorporate user feedback, “zoom in” on relevant patterns, reduce false positives, and provide local users with actionable insights based on their own criteria for what is, and is not, relevant.An overview of MUSES is shown in MUSES uses a new variant of topic modeling to learn syndrome categories directly from the data. Topic models are a set of algorithms that automatically summarize the main themes, or topics, contained in large collections of documents. The most widely used topic modeling approach, latent Dirichlet allocation (LDA), models topics as probability distributions over words and documents as probability distributions over these topics . This dataset has more than 28 million ED cases from 53 NYC hospitals during 2010–2016. For each hospital, we have data on the patients’ free-text chief complaint, date and time of arrival, age group, gender, and discharge International Classification of Disease–9 (ICD-9) diagnosis code. Public health practitioners at NYC’s Department of Health and Mental Hygiene (DOHMH) performed a blinded evaluation of the top 500 highest-scoring clusters detected over the 6-year time period by our method and by a competing, state-of-the-art, keyword-based approach. For each of these clusters, the evaluators indicated if the cluster (i) represents a meaningful collection of cases and (ii) is, in their judgement, highly relevant to public health . For example, clusters related to “bacterial meningitis” and “synthetic drug use” were rated as highly relevant, clusters related to “motor vehicle accidents” were rated as meaningful but not highly relevant, and clusters resulting from misspellings or common words (such as “left”) were rated as not meaningful. We note that the evaluation was blinded (cluster lists for the two methods were merged and shuffled) so that the public health practitioner was not aware which method reported a given cluster or where that cluster ranked on its top 500 list.The blinded evaluation by DOHMH demonstrated that our method correctly identifies a larger number of events of interest to public health departments than the baseline method. We observe that 320 (64%) of the top 500 results from MUSES corresponded to meaningful health events, while the keyword-based method only detected 246 such events (49.2%). In addition, to determine how our approach might provide situational awareness of emerging health concerns following a natural disaster, we examined the clusters identified by our approach in the week following 29 October 2012, when Hurricane Sandy struck NYC and caused a historic level of damage. These results show a temporal progression of detected clusters from acute cases related to falls and shortness of breath, to mental health issues like depression and anxiety, to chronic health issues that require maintenance procedures, like dialysis and methadone distribution. Such procedures are typically handled in outpatient clinics but were displaced to EDs when clinics were closed because of storm damage and power outages. We note that DOHMH epidemiologists manually inspected hospital ED data immediately following Hurricane Sandy; noticed an increase in the words “methadone,” “dialysis,” and “oxygen”; and created a “needs medication” syndrome  approach. During the initial evaluation, DOHMH practitioners indicated that 102 of MUSES’ 200 highest-scoring clusters represented events that were meaningful collections of cases but not specifically relevant to their jurisdiction’s needs for the system, including 28 clusters related to motor vehicle accidents, 12 related to medical evaluations or clearances, and 8 related to alcohol intoxication. With a PITL approach, the public health user could mark the first identified occurrence of a “motor vehicle accident” as irrelevant to that particular health department, enabling the system to ignore or de-emphasize future instances of such clusters and to focus attention on known and relevant event types, as well as those that correspond to novel, previously unseen events. Human in the loop topic modeling has also been shown to increase topics’ interpretability, improve users’ ability to find information in a large corpus, and encode expert knowledge  The PITL model outperforms the fixed model with respect to precision and the number of detected events of interest; (ii) the performance gap between the PITL and fixed models increases monotonically as a function of the number of labeled clusters used as training data by the PITL model; (iii) after an initial labeling of a cluster as a topic to be ignored, the PITL model will avoid presenting similar clusters to the user in the future, thus reducing false positives as compared to the fixed model; and (iv) after an initial labeling of a cluster as a relevant topic to be monitored, the PITL model will have higher power to detect future instances of that topic. During the 19 periods included in the experiment, the PITL model detected 49 highly relevant clusters, a 53% increase over the 32 detected by the fixed model. Because the fixed model could relearn an emerging topic that is similar to a monitored topic incorporated into the PITL model, if the cluster’s signal is sufficiently strong, then both models will detect the event. Nevertheless, as shown in Thus, we observe that the PITL MUSES model, incorporating monitored and ignored topics learned from user feedback, has improved ability to detect novel events, reduced false-positive rate, and can present users with more examples of clusters in which they have previously expressed high interest. Because PITL iteratively adds ignored and monitored topics to the model, and the emerging topics are chosen to be maximally different from these, it is able to better distinguish novel events from the known syndromes and patterns in the data. Furthermore, if the words in a cluster of documents are well represented by an ignored topic, they have a high likelihood of being assigned to this existing topic. Since we do not scan over subsets that include the ignored static topics, these clusters are unlikely to be shown to users, which reduce the false-positive rate. Conversely, because any documents that are closely aligned to one of the monitored topics have a high likelihood of being assigned to this monitored topic, fewer cases will be required to detect and report these events.The first wave of the COVID-19 pandemic hit NYC in March and April 2020 with catastrophic public health impacts. The city’s first COVID case was confirmed on 1 March, and by 30 April, there were over 174,000 confirmed cases and nearly 15,000 deaths, approximately one-fourth of the entire U.S. death toll to that point  and maps those cases to the emerging topics, enabling the cluster to be detected.As a robustness check, we evaluated MUSES with three different numbers of static topics  and compared the clusters detected (both for emerging topics and monitored static topics) in each case. The three variants produced extremely similar sets of detected clusters: The top 15 clusters for 10 and 25 static topics matched exactly, with minor differences in score (and thus some reordering of the cluster ranking), as well as minor differences in the age ranges included (and thus some differences in the precise set of cases included in each cluster). Fourteen of the top 17 clusters for 50 static topics also matched these 15 clusters, again with minor differences in score and cluster composition. While these results demonstrate that the number of static topics did not substantially affect MUSES’ ability to detect novel emerging clusters, some differences were observed in the clusters identified by scanning over monitored static topics. For 25 and 50 static topics, the same cluster of influenza-like respiratory illness on 31 March scored in the top 30 clusters, while for 10 static topics, no monitored static clusters scored even remotely close to the top 30. This difference was most likely due to the more focused topic distributions learned for larger numbers of static topics: Influenza-like respiratory illness formed its own topic for 25 and 50 static topics, while for 10 static topics, it was merged into a single topic with flu-like symptoms, cough, and fever. In addition, for 50 static topics, two other monitored clusters scored in the top 30: one cluster of 26 cases of flu-like symptoms in a 2-hour period on 27 March, and one cluster of 18 cough and fever cases in a 3-hour period on 21 March. Each of these two clusters was concurrent with a large, high-scoring novel cluster in the same hospital. While the assignment of COVID cases to static topics substantially reduced the score of the novel cluster for 1 hour of data, MUSES identified those cases as part of the larger novel cluster in the following hour, and thus neither timeliness nor accuracy of detection was significantly affected.While the above results demonstrate the potential utility of MUSES for identifying rare and novel events of public health interest, we now consider various limitations of the method that might reduce its ability to facilitate targeted and timely public health interventions. First, lags in data collection, preprocessing, analysis, or communication of results may affect timeliness, and thus effective use of MUSES depends both on a well-developed data infrastructure and the availability of public health practitioners to respond rapidly to the detected clusters. Second, false-positive clusters could result from repeated typographical errors by a particular triage nurse, hospital EHR changes and upgrades, or the use of new or unusual terminology to describe cases within a given hospital. While such clusters can easily be ignored, they may increase public health practitioners’ workload and potentially cause more relevant clusters to be overlooked. Thus, we have implemented data cleaning, including correction of common misspellings, as a preprocessing step for MUSES (as described below). Terminology changes could be incorporated either by adding them as ignored topics in the PITL model or by recomputing the static topics at regular intervals, as discussed below. Third, false negatives  could result from multiple sources of error. Chief among these are sampling bias and recording bias, since not everyone who has a particular symptom presents at the ED; those patients who do present may describe their symptoms differently, and different triage nurses may record them differently. ED usage may differ substantially between patient subpopulations depending on geographic, demographic, and socioeconomic characteristics, including factors such as access to care and insurance coverage. Given these biases, MUSES should not be used to perform population-level inferences like burden-of-disease estimation, nor should absence of a detected cluster be construed as an indicator that an event is not present. Rather, MUSES should be used as an exploratory data analysis tool, to identify potentially relevant case clusters that public health practitioners may otherwise have missed.sic]), they are likely to get grouped together into a single topic, mitigating this loss of detection power. In addition, an emerging pattern of cases may be grouped into an existing static topic rather than forming its own emerging topic, if it has too much overlap (in the sets of words used) with the existing topics. This incorrect grouping will lead to false negatives since the static topics are typically not included in the scan step. Possible solutions include using presyndromic surveillance as a complement to existing syndromic surveillance systems, which can pick up patterns of known syndromes, scanning over static as well as emerging topics, or using the PITL approach to designate certain static topics to be monitored rather than ignored. Last, our contrastive topic modeling approach is a randomized rather than deterministic algorithm, and thus MUSES is not guaranteed to identify identical clusters each time it is run on the same or similar data. However, we find in practice that the topics, and the resulting detected clusters, are highly consistent and robust to random variation when the amount of training data is large  and when the signal is strong . For example, we ran MUSES on a 90% subsample of the original data from March to April 2020 and compared the top 30 clusters in the original data with the top 30 clusters in the subsampled data. We observed that 22 of 30 clusters in each list matched a cluster in the other list , while the remaining clusters either narrowly missed the top 30 in the other list, or were narrowly beaten by a different cluster during that hour.While MUSES does not assume or require a representative sample for detection, its statistical power to detect a given event will depend greatly on whether the affected subpopulation is overrepresented or underrepresented in the ED data, as well as the extent to which the resulting ED chief complaints use similar sets of words to describe each case. For example, if a newly emerging event is referred to using different terminology in different hospitals, then cases from different hospitals may be assigned to different emerging topics, potentially leading to both missed cases (since each topic’s case cluster will omit the cases assigned to other topics) and reduced detection power (since fewer cases will result in a lower score). Similar losses of power may occur due to typographical errors (though preprocessing will correct some of these) or inconsistent usage within a single hospital. However, if the distinct terms co-occur with each other  or co-occur with the same other terms  from hospital EDs to health departments are necessary for both syndromic and presyndromic surveillance and are already in place for many jurisdictions. For example, NYC DOHMH’s Syndromic Surveillance Unit in their Bureau of Communicable Disease collects data on a daily basis from all 53 NYC EDs and monitors case counts of common syndromes such as influenza-like illness, respiratory illness, and gastrointestinal illness. For presyndromic surveillance, the critical data fields for each hospital to collect and send to their local health department are the date, time, and free-text chief complaint for each ED case; additional data such as ICD codes, and demographics such as age and gender, can enhance both detection and follow-up investigation of clusters. An automated process could run MUSES daily on the most recent 24 hours of ED visit data, typically requiring no more than 20 to 30 min for the contrastive topic modeling and scanning steps and have results ready for practitioners to analyze each morning. Practitioners could peruse the top-scoring clusters, and ideally provide feedback, through the visualization interface each day, or only on days when the score exceeded some fixed threshold. This process would take no more than a few minutes, unless a cluster was deemed worthy of follow-up investigation. While monitored and ignored topics would be updated automatically from user feedback, it would also be desirable to update the static topics  at regular intervals, e.g., once every few months, to account for changes in case distribution or data entry practices. Last, we recommend using MUSES as a complement, rather than a substitute, to existing practices such as notifiable disease reporting and syndromic surveillance, as these existing approaches would be more effective for identifying patterns of known disease types and commonly occurring syndromes respectively. The relative portions of the public health workflow devoted to these tasks would be situationally dependent. For example, during the peak of the COVID pandemic, public health resources were almost entirely devoted to COVID response, while presyndromic surveillance could have been used in a more limited and focused way to identify newly emerging symptom patterns among patients with COVID.MUSES builds upon new methodological approaches for syndrome discovery, cluster detection, and learning from user feedback to offer an innovative, presyndromic surveillance system that facilitates early detection and investigation of events of public health concern. Evaluation results from NYC DOHMH demonstrate the power of our detection methodology for accurately identifying clusters that are meaningful and relevant to local public health users, substantially improving the accuracy and specificity of detection as compared to existing state-of-the-art approaches. With the potential to enhance day-to-day situational awareness, to enable early detection of emerging biothreats during an emergency, and to provide a “safety net” to identify and investigate newly emerging and previously unseen events that existing systems would fail to detect, presyndromic surveillance is a critical next step for improved public health practice.To clean the data, we first used the Emergency Medical Text Processor (EMT-P), an open-source, natural language preprocessing system , learned from the data.MUSES uses a contrastive topic model to learn syndromes that correspond to rare diseases or novel emerging biothreats. This extension of the LDA topic model learns two sets of topics: a set of k’s distribution over words, φk, and each document d’s distribution over the KS static topics, θd, are drawn from Dirichlet distributions with hyperparameters β and α, respectively. The Dirichlet is a distribution over the probability simplex and is the conjugate prior of the multinomial distribution. From there, each word n in each document d is assumed to be generated by first drawing a topic assignment zd,n ~ multinomial(θd) and then a word assignment wd,n ~ multinomial .We learn the static topics by fitting a topic model to historical data using the standard LDA approach. To define a statistical model of the topics’ distributions over words and the documents’ distributions over topics, LDA makes a set of assumptions about how the data were generated. The standard generative model used in LDA assumes that each topic k and document-topic distributions θd are latent (unobserved) and must be inferred from the data through the conditional distribution P. While this posterior cannot be found through exact methods, there are a variety of methods that can be used to perform inference. MUSES uses collapsed Gibbs sampling, a common Markov Chain Monte Carlo approach, which is widely used for LDA models +Ksαwhere nd that is observed and remains fixed at the levels learned by the static LDA model.1) Each static topic φV) that is given by 2) Each emerging topic d has a distribution θd over static and emerging topics (a vector of length KS + KE) that is given by θd ~ Dirichlet(α).3) Each document wd,n in document d, a topic assignment zd,n is drawn from Multinomial(θd). If the topic assignment corresponds to a static topic, a word assignment is drawn from Multinomial. If the topic assignment corresponds to an emerging topic, a word assignment is drawn from 4) For each word Note that the presence of the fixed static topics distinguishes this model and set of assumptions from standard topic modeling. Given these generative assumptions, the joint distribution isK = KS + KE topics. Typically, we assume KS = 25 static topics and KE = 25 emerging topics. The initial topic assignments are based on the topics φ learned by performing inference on the historical corpus and the most recent collection of documents. That is, wd,n is the nth word in document d, zd,n is the topic assignment of wd,n, and φk is determined as follows: If k is a historical static topic, φk was learned by applying standard LDA to a large set of historical data, and if k is an emerging topic, φk was learned by applying standard LDA to the most recent set of data. After making the initial topic assignments, we proceed with the Gibbs sampling procedure described in the previous section, using the combined set of static and emerging topics, but only update φk using k is an emerging topic, thus keeping all static topics fixed throughout the learning process. When this inference is complete, we refer to the second set of re-optimized φ′ as emerging topics.To learn the emerging topics’ distribution over words and the documents’ distributions over static and emerging topics, we perform Gibbs sampling with a few modifications. Here, we consider a total of We note that time is not explicitly represented in the Emerging Topic LDA Model . Rather,k has a distribution over words It is straightforward to incorporate ignored and monitored static topics into the Emerging Topic Model. We assume that each ignored and monitored static topic SAfter learning newly emerging syndromes from the chief complaint data, we use a multidimensional extension of spatial scan statistics to identify localized case clusters corresponding to these topics. Kulldorff’s spatial scan approach considers circular geographic search regions that are centered at each monitored location and have varying radii, allowing for detection of both spatially compact and dispersed clusters. Extensions to this method consider a variety of types of geographic search regions, including rectangles, ellipses, and more general search regions over subsets of the data , has demographic characteristics included in {δ1,1, δ1,2, …, δp1,} × … × {δj,1, δj,2, …, δj,s}, and has a chief complaint that maps to a given emerging topic or monitored static topic . To map each chief complaint to one of the learned syndromes, we follow  is that there is a cluster of some (emerging or monitored static) topic affecting search group S. We assume that if there is no cluster, count ci,j,k of this topic at time i, location j, and among demographic group k will be distributed according to a Poisson distribution ci,j,k ~ Poisson , where bi,j,k is a baseline or expected count for this topic during the same time frame and among the same demographic group of patients. If these patients are affected by a cluster, we expect that there will be a multiplicative increase in counts as compared to the baseline; i.e., the count will be distributed as ci,j,k ~ Poisson  for some constant q > 1, where q is estimated by maximum likelihood. Given these assumptions, the formula for the log-likelihood ratio score F(S) simplifies toFor each search group, we compute the log-likelihood ratio scorei is given by ib = (ACh + ACoh)/2, where ACh is the average hourly case count over the last 28 days during the same hour as the hour in time period i, and ACoh is the average hourly case count over the last 28 days during all other hours of the day. We use F(S) to identify the highest-scoring clusters of cases that should be reported to users as potential events of interest.Here, We use the log-likelihood ratio scan statistics to identify anomalous clusters in both MUSES and the keyword-based comparison method. While keyword-based approaches have used a variety of statistical methods for this task, this allows us to isolate and study the impact of learning syndromes versus considering each keyword individually.For the first blinded user study, we ran both MUSES (fixed model) and the competing keyword-based approach for each hour of data over the entire 6-year period from 2010 to 2016. For a given hour of data, we used a 3-hour moving window (that hour and the two previous hours) to learn emerging topics and scanned over clusters from 1 to 3 hours in duration. The static model for the first case study was learned from a 10% sample of the entire 6 years of data. For this user study, we learned separate topic models for each NYC hospital, with 25 static and 25 emerging topics for most of the hospitals, and up to 50 static topics for hospitals with particularly large patient populations.For the second blinded user study, we ran both the fixed and PITL models for each hour of data in 2-week increments from 1 January through 30 September 2016. For a given hour of data, we used a 3-hour moving window (that hour and the two previous hours) to learn emerging topics and scanned over clusters from 1 to 3 hours in duration. The initial static topic model (for both fixed and PITL models) was learned from the previous year of data, 1 January through 31 December 2015. For this user study, we learned a single topic model across all NYC hospitals, using 25 static and 25 emerging topics. The PITL model’s static topics were updated after each 2-week period (adding monitored and ignored static topics as labeled by the user), while the fixed model’s static topics were not updated.x is given byc is a cluster, iI is the set of clusters detected by the model and labeled “to ignore” by the practitioner in period i, t is a topic, ISTi is the set of ignored static topics at the start of period i, similarity is a similarity measure, and τ is a similarity threshold. Here, we measure the similarity between a detected cluster c (with a topic ct) and an ignored topic w in the cluster’s topic and the ignored topic, respectively. For example, the similarity between a detected cluster with a topic that places probabilities of  on the words  and an ignored topic that places probabilities of  on the words  would be min + min  + min  + min  = 0.66. A similarity threshold of τ = 0.6 was used for this analysis.To understand why the PITL model offers improvements over the fixed model, we first consider our third hypothesis, which predicted that after an initial labeling of a cluster as a topic to be ignored, the PITL model will avoid presenting similar clusters to the user in the future, thus reducing false positives as compared to the fixed model. We evaluate this hypothesis by measuring the total number of clusters detected by the model in each period that have topics similar to a topic that was previously detected and labeled “to ignore” by the public health practitioner. That is, the number of previously incorporated ignored (PII) topics shown to the user in period iM is the set of clusters detected by the model and labeled “to monitor” by the practitioner in period i, MSTi is the set of monitored static topics at the start of period i, and all other values are defined as in Our final hypothesis predicts that after an initial labeling of a cluster as a relevant topic to be monitored, the PITL model will have higher power to detect future instances of that topic. We evaluate whether the PITL model is able to identify more clusters that are similar to those the practitioner has labeled “to monitor” than the fixed model by measuring


People over 40 years old , from only-child families , with household indebtedness , or difficulty falling asleep  had risk factors of suicidal ideation. (4) Conclusions: The physical and mental health of individuals’ family members are related to their suicidal ideation, and their lineal consanguinities’ physical and mental health are not related to suicidal ideation. These findings imply the different associations between family environment, genetic factors, and suicidal ideation. Family members’ health should be considered as a factor to prevent and control suicidal behaviors, including suicidal ideation.(1) Background: Despite the verified relationship between relatives’ characteristics and individual suicidal ideation, few studies have discussed the role of family members and lineal consanguinity independently according to whether they live together with the individuals or not. (2) Methods: The data in this study were collected in November 2019 and identified rural adults over 18 years old in Shandong as the survey objects, with a total of 879 valid cases included in this survey. Logistic regression analysis was employed to examine the risk factors affecting adults’ suicidal ideation and differentiate the effects of a family member and lineal consanguinity’s physical and mental health. Relatives’ physical and mental health were estimated by three aspects: whether they were suffering from chronic diseases, mental illness, or alcoholism. (3) Results: The study showed that a family member’s physical (OR = 2.303,  According to the World Health Organization (WHO)’s estimation, more than 700,000 people die by suicide each year, which means that approximately one person dies by suicide every 40 s in the world . The latMany studies have been conducted in recent decades to explore the factors associated with suicidal ideation among different populations ,16,17,18In addition, many studies further explored the role of relatives’ characteristics on suicidal ideation. For example, family conflicts, parenting styles, and separated parents were shown to be elements that result in unhealthy emotions and even suicidal behaviors ,35,36,37Regarding FMs, various studies have found that family characteristics are associated with individuals’ suicidal ideation. Previous studies proved that poor family functioning, family problems, and violence by family members could increase the incidence of suicidal ideation ,45,46,47For LCs, however, little research has been committed to exploring their effects on suicidal ideation. Only in studies of suicide was the influence of LC’s behavior noticed. For example, a slew of studies showed that suicidal behavior had a tendency for family aggregation ,58, whicAlthough the effect of the behavior of a LC on suicide has been identified, few studies have aimed to find the association between a LC’s health and an individual’s suicidal ideation. Furthermore, most studies aimed to observe the influence of relatives’ characteristics on an underage group, rather than adults, but this study focused on the adult population and tried to seek out a new way to prevent adult suicide. In the end, there were few studies examining the differences in the effect of FMs and LCs on suicidal ideation from the perspective of environmental impact. Therefore, the aim of the present study was to investigate the risk factors of suicidal ideation and distinguish the influences of FM’s health and LC’s health with the hope of providing evidence for suicide prevention among rural adults.The data in this study were collected in November 2019. Respondents of this survey are adults over 18 years of age from the Shandong rural areas in China. Data was collected from Taierzhuang of Shandong province. Shandong, a major province of economy and agriculture, is located in eastern China. Seventeen cities are included in Shandong, and Taierzhuang District, seated in the south of Shandong province, belongs to Zaozhuang City. According to data from the seventh census in China, the resident population of the whole Taierzhuang District is 305,102, and inhabitants residing in rural regions account for 53.72% of the whole population . Five toA face-to-face interview was applied in process of collecting data. Interviewers were postgraduate students who had received professional training and were required to understand the whole research. Before the investigation, respondents and their families agreed to provide relevant information and signed a written informed consent form. As for collecting data, interviewers filled in questionnaires following the answers from the respondents. After the investigation, more than two students inspected the contents and modified the wrong or missing items.The dependent variable of this survey is suicidal ideation. It is evaluated by the question “Have you ever seriously thought over committing suicide?” There existed two answers to this question, “yes” or “no”. Respondents were required to answer this question honestly based on if this thought had ever occurred in their whole life. This question had been used to evaluate suicidal ideation in many previous studies, such as in the exploration of suicidal ideation in college students and adults ,35.According to Chinese traditional habits, a FM refers to relatives living together with individuals currently, and a LC includes relatives who do not live together as adults but have blood relationships, such as uncles, brothers, and sisters. Investigators were asked to explain the differences between two types of relatives in the process of inquiring since the difference between living together and being related needed to be focused on and differentiated.The health condition of relatives was estimated separately in this study. For FMs, the answer to the question “If your FM suffer from severe chronic diseases?” was used to represent physical health. As for mental health, alcohol use disorders were considered as one mental disorder based on a report from WHO . TherefoThe questionnaire also involved basic socio-demographic information, such as gender, age, occupation, marriage status, education level, and family composition. Gender was divided into two categories: male and female. Age was obtained by subtracting the year of birth from the current year and classified as 18–40 and >40 years old. Occupation types included farmers, students, personnel of public institutions, businessmen, and so on, but the occupation was reclassified into two categories, “freelancer” and “others”, for the convenience of data analysis. Marriage status was represented by married and other conditions “unmarried, divorced and widowed”. Considering the low educational level in rural areas, junior high school education was selected as the dividing line, and results were classified into primary school education and below and junior high school education level and above. The familial composition was evaluated by one question “Were you an only child?” In addition to the above variables, household indebtedness and sleeping difficulty were also risk factors. The household indebtedness condition was estimated by the question “Was your family in debt?”, with two choices of answers, “yes” or “no”. Cannot fall asleep within 30 min was defined as difficulty falling asleep according to the PSQI, and there were four levels of the answer, “not”, “once a week”, “twice a week”, and “three times a week and above”. Similarly, we grouped the answers into two categories “yes” or “no” in the analysis of data.p-value was less than 0.05.IBM SPSS Statistics 26.0 was the main software for analyzing data. The Chi-square test was used to describe social-demographic characteristics and discover the single risk factors of suicidal ideation. Logistic regression analysis, differing from single-factor analysis, was applied to examine the effects of multiple independent variables on suicidal ideation. We coded all answers as “1” and “0” and considered the results to be statistically significant when the p < 0.001) were associated with suicidal ideation. After classification, however, only having a FM with a chronic disease , mental illness , or alcoholism  were considered as risk factors.In p < 0.001), had a higher prevalence of suicidal ideation. While comparing people with a junior high school degree and above , those with fewer years of education had a higher prevalence of suicidal ideation. Comparisons were also conducted between only-child families and multiple-child families; the result showed that people from only-child families  had a higher incidence of suicidal ideation. Regarding other conditions, risk factors included household indebtedness  and falling asleep with difficulty .Regarding other factors in p = 0.026), from an only-child family , household indebtedness , difficulty falling asleep , and relatives with chronic disease  were associated with suicidal ideation. In Model 2, we classified the relatives further and included the variables on FM’s health and LC’s health. The results showed that an age >40 , from an only child family , household indebtedness , difficulty falling asleep , and a FM with chronic illness  or mental illness  were risk factors of suicidal ideation.For further analysis of factors related to suicidal ideation in rural residents, suicidal ideation as the dependent variable, and demographic characteristics, sleep status, and relatives’ health as the independent variables, were included in Model 1 of the logistic regression analysis. All of the results are shown in In this study, the main objective was to identify the influencing factors of suicidal ideation and differentiate the effect of FMs’ and LCs’ health on suicidal ideation among rural adults. Results showed that the prevalence of suicidal ideation in rural residents was 6.83% in this survey, which was close to the estimation of other studies, such as research in rural areas of Shandong Province and Zhejiang Province ,64,65. TCollectively, this study observed that relatives with chronic disease were associated with individuals’ suicidal ideation firstly, which was consistent with results concluded by previous research. Regarding this, relatives’ physical health was determined to be a risk factor affecting suicidal ideation in past studies ,49. The In the comparison of FMs and LCs, we found that FMs who suffer from chronic disease and mental illness had a strong connection with suicidal ideation, but a LC’s health was not associated with it. The greatest distinction between FMs and LCs lay in whether they live with the individual, that is, FMs share the living environment and LCs do not. Further exploration demonstrated that a safe family, public, and hospital environment were necessary for the prevention of suicide in adults. Relatedly, the environment was found to be a factor associated with the suicide rate of the elderly ,76. StudRegarding other factors, the present study also found that there was a greater possibility of suicidal ideation in people over 40 years old. Previous studies also indicated that the prevalence of suicidal ideation in the middle-aged and elderly group was associated with loneliness, household financial problems, and poor perceived health ,85. ThisCollectively, a FM’s physical and mental health status, as one kind of factor of the living environment, could affect an individual’s mood and behaviors. Specific reasons may be the stress as a caregiver and negative emotions caused by the disease while living together. Furthermore, people over 40 years old, people from only-child families, people with household indebtedness, and people with difficulty falling asleep were considered to be in high-risk groups who were more likely to have suicidal ideation.In this study, certain limitations should be considered. Firstly, the study only opened an investigation and collected data from rural areas of Taierzhuang District, and we should be cautious when interpreting the findings into other populations and regions. Secondly, the data of this study came from the self-reporting of respondents, which may have recall bias. Next, although on a large scale, differences between the effect of FMs and LCs on suicidal ideation were explored, but exact reasons for these differences were not evidenced in this study. Finally, the present study did not discover the effects of FMs’ and LCs’ alcoholism on suicidal ideation in adults, so further validation is required in future studies.In conclusion, the prevalence of suicidal ideation in Shandong rural adults was 6.83%. Before categorization, only relatives with chronic disease were a risk factor for suicidal ideation. Comparing the influences of relatives’ health, results indicated that FMs who suffered from chronic disease and mental illness made an impact on suicidal ideation, and an evident correlation was not found in LCs. This difference reminded us that the psychological condition of adults with a FM suffering from health disorders should be monitored closely. In addition to studying the impact of relatives’ health on suicidal ideation, there needs to be more attention paid to people over 40 years old, people from only-child families, people with household indebtedness, and people with difficulty initiating sleep.Focusing on adults with a FM suffering from physical and mental illness and publicizing the influence of the living environment on suicidal ideation are crucial. Hence, more measures need to be taken for reducing suicidal ideation by the melioration of FMs’ physical and mental health. More action needs to be taken in the community after identifying the impact of family members’ health on an individual’s suicidal ideation. The government should encourage the community to pay more attention to the mental health of a patient’s family members for the purpose of suicide prevention. Further, doctors need to focus on the role of relatives in the treatment of suicide, in order to reduce the suicide rate of rural residents, make suicide prevention and intervention plans based on the home environment, provide more social and psychological services, and improve family happiness for rural adults.


Mahāmudrā practice from Tibetan Buddhism. This third step represents a heuristic for evaluating the external coherence of the presented model. With this, the aim is to point toward a principled enactive view of non-dual meditative practice. In drawing the implications of the presented model, this article ends with an outlook toward next steps for further developing a research agenda that may fully address the concrete elements of non-dual practices.Within a variety of contemplative traditions, non-dual-oriented practices were developed to evoke an experiential shift into a mode of experiencing in which the cognitive structures of self-other and subject–object subside. These practices serve to de-reify the enactment of an observing witness which is usually experienced as separate from the objects of awareness. While several contemplative traditions, such as Zen, Mahāmudrā, Dzogchen, and Advaita Vedanta emphasize the importance of such a non-dual insight for the cultivation of genuine wellbeing, only very few attempts in contemplative science have turned toward the study of non-dual-oriented practices. This article starts from a recently developed theoretical cognitive science framework that models the requirements of a temporary experiential shift into a mode of experiencing free from cognitive subject–object structure. This model inspired by the enactive approach contributes theoretically grounded hypotheses for the much-needed rigorous study of non-dual practices and non-dual experiences. To do so, three steps are taken: first, common elements of non-dual-oriented practices are outlined. Second, the main ideas of enactive cognitive science are presented including a principled theoretical model of what is required for a shift to a pure non-dual experience, that is, an experiential mode that is unbound by subject–object duality. Third, this synthesized theoretical model of the requirements for the recognition of the non-dual is then compared with a specific non-dual style of meditation practice, namely,  While research into mindfulness had gained more and more scientific interest, there is a major need to expand scientific research beyond a narrow focus on mindfulness meditation. One of these styles of meditation that has yet received little attention in scientific research but is highly relevant is non-dual meditative practice  can here be preliminarily defined as the flipside of co-dependent arising: whatever appears springs from a complex dynamic of relations, without substantial ground.These core ideas of the enactive approach on autonomy, sense-making and adaptivity all taken together, imply that the world and ourselves are dependently arising processes. They lack any substantial ground. Both, the world and ourselves are For a more comprehensive but brief overview of the key concepts in the enactive approach see The Embodied Mind has shown to be open for correctives. In its revised edition, Evan Thompson and Eleonor Rosch elaborated their correctives to the enactive approach since its first publication. This openness for correctives is to be seen as “vital signs” or “indicators of the vitality of the evolutionary arc of thinking and praxis” inherent in the enactive approach  and phase 2 enaction.In approaching this central stepping stone, a starting point for a definition of “knowing groundlessness,” that is, “non-dual experience” is found at Phase 1 enaction corresponds to the aforementioned common enactive notion of sense-making. It comprises a knowing of a world that is related to performing actions relevant to maintaining the living body. It is dualistic and involves a subject–object distinction . Non-adaptivity means that one does not regulate itself regarding the limitations of its viability. It does not judge its experiences as good, bad, or neutral. Therefore, it does not approach, avoid, or ignore any aspect of its experience. This might be referred to as a state of unconditional acceptance. Non-dual reflexive knowing  means that one is just aware via phase 2 enaction. One effortlessly recognizes one’s current acts of sense-making as acts of sense-making. This recognition, importantly lacks sense of observer and observed and is non-dual. In the transition from toward a purely non-dual experience, these two requirements are met: Current acts of sense-making are experienced. Through the unconditionally accepting attitude, no further adaptivity is added. Therefore, sense-making is not added. In continuation of this process, sense-making progressively ceases. As a consequence, the reflexive knowing capacity (phase 2 enaction) is less and less obscured. This may lead to a moment when phase 2 enaction is not obscured anymore. Then this awareness can recognize itself: “[e]xperience experiences itself, non-dually. This is a moment of knowing groundlessness” .theoretical analysis based on concepts from the enactive approach, it remains yet open to which extent these hypothesis are viable. A method for evaluating the coherence of these concrete hypotheses is required. This is the purpose of this article.As these hypotheses are derived from a However, the scientific method has only limited access to matters concerning consciousness: “Consciousness itself has not been and cannot be observed through the scientific method, because the scientific method gives us no direct and independent access to consciousness itself. So the scientific method cannot have the final say on matters concerning consciousness” , p. 94.Therefore, this article follows a more heuristic path toward estimating the viability of the hypotheses on what is required for an experiential shift to a direct non-dual experience: an assessment of the hypotheses’ external validity. Therefore, the aim of this paper is to compare this enactive approach to structural requirements of non-dual experiences with concrete practice instructions from a certain non-dual practice tradition. More specifically, a practice tradition from Tibetan Buddhism is chosen, namely, Mahāmudrā practice.not to compare the enactive view in general with a Buddhist view or philosophy. As aforementioned, the enactive approach is importantly inspired by Buddhist philosophy. Such a comparison might simply trace back the historic origins of the enactive approach rather than providing additional insights. However, this article follows a different aim. It does not compare the general enactive view with a Buddhist view. Instead, it compares new hypotheses generated from a recently developed conceptual expansion of the enactive view with practice instructions from a particular Buddhist style of meditation practice. Accordingly, the purpose of this paper is to contribute to a coherent expansion of the enactive view to the understanding of groundlessness and non-dual experience.Three clarifying remarks regarding the aim of this article need to made. First, the aim of this paper is not to use the enactive approach to prove Buddhism’s scientific viability. Instead, it aims at a comparative approach between a recent extension of the enactive view and a specific Buddhist practice. What are then its validity criteria? The validity of this comparison’s outcome does not follow scientific validity criteria but rather those validity criteria that also hold in philosophical discourses, such as coherence and transparency . These are important steps for non-trivially expanding the theoretical study of meditation to non-dual oriented practices.To which extent does the recently developed enactive view of the conditions for a shift into a non-dual mode of experience match the actual practice instructions from the Mahāmudrā tradition?Accordingly, this article’s research question is in direct correspondence to the aforementioned aim: via a rigorous comparison between the enactive theoretical model of the performative requirements for a non-dual experience with the specifics of non-dual-oriented Mahāmudrā practice instructions from Tibetan Buddhism. In the following, both levels of analyses from the recent enactive model are compared to Mahāmudrā practice.This central research question is approached In the previous section, we explored theoretically the transition process from sense-making to knowing groundlessness . It appears that this transition process can be practiced by human beings. Indeed, there are practices in several human cultural traditions that aim at exactly this momentary transition from sense-making to a pure non-dual experience.practice or Buddhist thought in general, we are going to focus on a very specific style of non-dual practice: Mahāmudrā.Accordingly, the guiding question of this section concerns the plausibility of the results from the first and the second level of analysis from the perspective of a specific non-dual practice tradition that aims at non-dual experiences: does the enactive description of the transition into a temporary non-dual experience match meditation instructions from non-dual traditions? In this article, rather than targeting Buddhist Mahāmudrā practice instructions are especially designed for guiding a practitioner into a “recognition of the non-dual” which is equivalent to “knowing groundlessness.” Therefore, those instructions can indicate the extent of the theory’s plausibility from an explicitly practice-oriented point of view. This is crucial for evaluating the external coherence of the recent enactive development on what a shift into a potential non-dual experience requires.Mahāmudrā practice is Yogācara, a non-dual philosophy. One important guiding question in this non-dual style of philosophy is about the experience of groundlessness: what does it mean to experience śūnyatā ? Moreover, this non-dual Buddhist philosophy can be regarded as being grounded in the lived experiences of actual practitioners. Therefore, the answers from various strands of this non-dual Buddhist approach can provide a hint at the context-dependent plausibility of the conclusions from the model of what a shift into a potential non-dual experience requires from within a purely conceptual enactive perspective. This comparison has important potential for additionally grounding an enactive understanding of a non-dual style of meditation practice.One philosophy that underlies Accordingly, the guiding question for this section concerns the degree to which the presented enactive approach of non-dual experience and Mahāmudrā practice instructions match: is there a correspondence between the enactive description of what a shift to a non-dual experience requires and practice instructions from the Mahāmudrā tradition?cf. cf. The aim of this subsection is to compare each stage of the first level of analysis of the enactive account of a shift to a non-dual experience cf.  with anaIn the transition process toward a pure non-dual experience , adaptive sense-making has been chosen as the point of departure. It is what the enactive approach refers to as cognition. This sense-making is always based in its underlying activity of approach and avoidance that is coined “adaptivity” .samsara. The conceptual correspondence between adaptive sense-making (or phase 1 enaction) from the enactive approach and the Buddhist notion of samsara is summarized by Eleonor Rosch in her introduction to the revised version of The Embodied Mind:In Buddhist contexts, a corresponding notion is the one of [f]rom the Buddhist point of view, both phase 1 enaction and the skandhas are portraits of the confused and ignorant body, mind, and world that is called samsara, that is, the wheel of life through which sentient beings cycle in ignorance and suffering (see chapters 4 and 6). The good news is that there is an alternative. There is another mode of knowing not based on an observer and observed. This ushers in phase 2 of enaction, what in the book we call groundlessness (chapter 10) . This point is reflected in the following statement by Chökyi Nyima Rinpoche, a contemporary Buddhist teacher in the Mahāmudrā and Dzogchen tradition:[u]nless we allow every single kind of conceptualization – of forming a notion of something, whether it is in a coarse way or a subtle way, shallow or profound - unless we allow all of that to dissolve, to simply evaporate, we do not clearly see our innate nature .samsara. In order to transition to “knowing groundlessness” one is required to simply let go of phase 1 enaction. This directly corresponds to the direction proposed in the recently developed enactive model for a shift into “knowing groundlessness”  is that Mahāmudrā does not involve anything to be abandoned (heya) or anything to be accomplished or adopted (upādeya)” , p. 262.houghts” , p. 261.houghts” , p. 136.The reason for such a need of non-abandoning and non-accomplishing is that judgments of that kind lead to further thought as it is reflected in another Mahāmudrā instruction: “If you really investigate this meditation approach, you will realize that to judge discursive thoughts as either good or bad is merely to engage in further discursive thinking” , p. 148.inhibit another requirement for thought to operate, namely, the approach/avoidance stance of an agent acting in the world”  but also “continuously maintaining the present awareness with undistracted mindfulness” , p. 165.as an act without adding sense-making or adaptivity. This allows sense-making to cease.In enaction speak, the transition process toward knowing groundlessness requires an experience of the current sense-making act. One needs to experience the current sense-making itself rang grol) that occurs when one ‘looks intently’ (cer gyis lta) at a thought”  is reflected in another crucial tool of Mahāmudrā practice, the “self-liberation of thought”: “[i]n Mahāmudrā terminology, this is known as the ‘self-liberation’  aims at allowing thoughts to vanish: “[s]imply by looking at itself, thought is pacified” , the Mahāmudrā instructions emphasize on two mental gestures that are directly equivalent to those two from the enactive synthesis: non-adaptivity (inhibiting an approach/avoidance stance of being an agent in the world) and non-dual reflexive knowing . Those are important hints toward the coherence between the theoretical insights from the enactive model described by Two aspects are to be emphasized at this point. First, the Mahāmudrā practice of “self-liberation of thought”  requires another mode of knowing that is non-intentional and non-propositional in contrast to common intentional propositional sense-making. This leads us to the analysis in stage 2.cf. As we have seen, Mahāmudrā practice instructions reflect the conclusions from the enactive model of the requirements for an experience of groundlessness, that is, of a direct non-dual experience cf. : for tranot involve adaptive sense-making but another mode of knowing: sustained non-propositional meta-awareness, that is, non-dual reflexive experiencing. The reason for this is simple: sense-making in this context would lead to an infinite regress resulting in constant additions of sense-making acts. Sense-making would be increased, not reduced. Therefore, another mode of knowing needs to be introduced to the enactive approach: non-dual knowing which is recognized in knowing groundlessness . Does this correspond to or rather contradict Mahāmudrā instructions?The key question here concerns the kind of knowing involved in this required act of reflexive knowing: is the current sense-making activity recognized through propositional intentional sense-making or somehow differently? By means of the inherent logic of the idea of sense-making from the enactive approach, gradual approach one begins by directing the mind to an object of attention  as an anchor (dran rtags) that minimally captures attention so as to inhibit capture by distractors” , this aspect of consciousness is non-dual in the sense that when information is obtained through reflexive awareness, it does not mean that a phenomenal sense of subjectivity is focusing on that information’s source as an object  as the second requirement of shifting toward knowing groundlessness  by reflexive non-dual awareness (svasaṃvitti). Those lead to self-liberation of thought (rang grol). At this, (1) the first requirement “non-adaptivity” translates into being “non-judgmental”; (2) the second requirement “non-dual reflexive knowing” (phase 2 enaction) translates into “looking intently” by reflexive non-dual awareness (svasaṃvitti). These two elements together lead to a decrease of sense-making which translates into the self-liberation of thought (rang grol). Those matches between the enactive model of non-dual practice  the same as “knowing groundlessness” or as a non-dual experience? From within the coherence of the enactive approach, the following distinction between non-dual reflexive knowing and knowing groundlessness has been derived: while non-dual reflexive knowing is already present during sense-making but is obscured by it, knowing groundlessness is the recognition of this non-dual reflexive knowing during an absence of sense-making.Is reflexive awareness . Also, this point of Mahāmudrā is in fascinating correspondence to the previously applied juxtaposition between non-dual reflexive knowing and knowing groundlessness: non-dual reflexive knowing is constantly present but is only recognized in a moment of knowing groundlessness when adaptive sense-making has ceased.experience descriptions of knowing groundlessness: what is it like to experience groundlessness? The traditional Mahāmudrā response to that question highlights two experiential aspects of groundlessness: emptiness and luminosity. In other words, realizing groundlessness is to see that the flow of experience itself is nothing other than the empty luminous mind. “Luminosity” in this regard denotes the “knowingness” aspect of consciousness whereas “emptiness” means that it is devoid of the structures that constitute subject and object, and even time and space: “[n]ot only is everything from the aggregate of forms to omniscient enlightenment unreal, empty and devoid of mental constructs; in addition, everything is luminosity” . Third, this description is inappropriate from within the “perspective” of knowing groundlessness. Fourth, none of the two perspectives is ultimately true. However, they make sense in different contexts.The second level of analysis provided the insight that the first level description is invalid from within this “perspective” of knowing groundlessness this exact knowing groundlessness can only be explored further when conceptual thinking is left behind.In the context of the “perspective” from within knowing groundlessness, language is an inappropriate method. Any use of language reintroduces sense-making. This necessarily interrupts a moment of knowing groundlessness. Therefore, language and knowing groundlessness are mutually exclusive. At this point, we have reached an end of linguistic description. Here, philosophical analysis is not useful anymore. From cf. cf. Saṃbandhaparikṣā  to Buddhist thought in the first place. Those similar conclusions are expressed in several passages of his Mūlamadhyamakakārikā. Let us have a look on some of those passages in detail.Is there a similarity of those conclusions to some forms of Buddhist philosophy? First, the most obvious correspondence is due to a direct use of a traditional Buddhist argument in the second level of analysis cf. . The neicf. translation by First, Nāgārjuna offers a similar criticism concerning the idea of relationality or circular establishment. Thereby, it is translatable to a criticism against the idea of co-emergence in the enactive approach. In chapter 10, verse 10, Nāgārjuna addresses this idea of co-dependence: “[i]f an entity x is established in dependence [on something else y], and in dependence on that very entity x there is established that y on which x’s establishment depends, then what is dependent on what?”  appears to be incoherent  turns out to be incoherent. From Nāgārjuna’s point of view, this is not a circular establishment but a failure to establish. If this argument by Nāgārjuna is accepted, all the enactive accounts of circular emergence  are failures of establishment. In order to establish them, those ideas prompt to talk about something else. It renders a form of avoidance to say that one simply does cf. translation by Mūlamadhyamakakārikā. However, the translators call for caution concerning this verse as it can easily be misunderstood. They elaborate on this relation between interdependence and emptiness in the following way:Second, in the second level of analysis see  this ana[t]o say of emptiness that it is a dependent concept is to say that it is like the chariot, a mere conceptual fiction. […] That is, emptiness is itself empty. Emptiness is not an ultimately real entity nor a property of ultimately real entities. Emptiness is no more than a useful way of conceptualizing experience  is a “dependent concept” does not mean that interdependence ultimately exists but rather that there is no possibility for an ultimate reality where things have an independent essence. Therefore, śūnyatā has no ultimate meaning, it is groundless itself: “[i]f something that is non-empty existed, then something that is empty might also exist. Nothing whatsoever exists that is non-empty; then how will the empty come to exist?” mptiness is taught by the conquerors as the expedient to get rid of all [metaphysical] views. But those for whom emptiness is a [metaphysical] view have been called incurable” , not populated by hypostatization, devoid of falsifying conceptualization, not having many separate meanings—this is the nature of reality” [Mūlamadhyamakakārikā, chapter 18, verse 9; cf. translation by Third, in the second level of analysis, it has been proposed that any use of language reintroduces sense-making. This necessarily interrupts a moment of knowing groundlessness. Therefore, language and knowing groundlessness are mutually exclusive. Accordingly, language keeps a practitioner from śūnyatā) is a dependent concept. On the other hand, groundlessness does not have an ultimate meaning. To say that it is a dependent concept is therefore also wrong since it is a statement concerning its existence. What does that mean? At this point, it is important to have in mind Nāgārjuna’s conception of truth. He and the Madhyamika philosophy distinguish two levels of truth, the relative and the ultimate. Those two truth levels are also mentioned by In making this step we are enabled to see an interesting split in the levels of philosophy by Nāgārjuna. There are two levels. On the one hand, Nāgārjuna stated positively that groundlessness  is the phenomenal world just as it appears—with chairs, people, species, and the coherence of those through time. Ultimate truth (paramartha) is the emptiness of that very same phenomenal world. The Tibetan term for relative truth, kundzop, captures the relation between the two imagistically; kundzop means all dressed up, outfitted, or costumed—that is, relative truth is sunyata (absolute truth) costumed in the brilliant colors of the phenomenal world .At this point, I will highlight the correspondences between the enactive theory of what a shift to knowing groundlessness requires and what Mahāmudrā practitioners in fact practice for facilitating such a shift. Especially interesting is that those correspondences occurred on both of the two levels, on the first level of analysis and on the second level of analysis. On the first level of analysis two main ingredients have been derived as being necessary for sense-making to cease and to know groundlessness: (1) non-adaptivity and (2) non-dual reflexive knowing. Both two predicted requirements for a shift from sense-making to knowing groundlessness find their direct equivalent in the non-dual Mahāmudrā practice and in its underlying philosophy: (1) non-judgment and (2) reflexive awareness .practice  from an enactive perspective.In order to approach this central aim of this article, an enactive approach has been presented which accounts for what might be required from a cognitive system to shift into an experiential mode of non-dual experience. This resulted in presenting two performative structural elements that are key for an experiential shift into a non-dual state: non-adaptivity and non-propositional meta-awareness . This has paved the way for the main step of this article: evaluating this enactive framework by comparison with concrete practice instructions from a non-dual meditation tradition: Mahāmudrā. This provides the core of an enactive approach to non-dual practice: non-dual meditative svasaṃvitti; rang rig). This is considered preliminary evidence that the provided description of the transition process makes sense in the context of a lived practice that aims at eliciting non-dual experiences. Interesting is also that the provided description from the second level of analysis is reflected in one way of reading Nāgārjuna’s Madhyamika philosophy.As a result, we have seen a close correspondence between an enactive prediction of what a shift to knowing groundlessness requires and what Mahāmudrā practitioners in fact practice for enabling such a shift: on the first level of analysis, we encountered that (1) non-adaptivity matches the emphasis in Mahāmudrā instructions on non-judgment. Also, (2) non-propositional meta-awareness  matches the emphasis in Mahāmudrā instructions on reflexive awareness  (1) build on a principled enactive meshwork of ideas and (2) match Mahāmudrā practice as one exemplary non-dual practice tradition. Therefore, principled hypotheses about what concrete experiential acts cause non-dual experiences are provided that may inform future scientific studies into the specifics of non-dual practices. This asks for operationalization of those two components: how to assess the extent to which a practitioner is non-judgmental  and to which extent the practitioner is reflexively aware and vigilant ? This asks for a methodological evaluation of how psychometric assessments, phenomenological in-depth interviews  and by the BIAL Foundation (No. 333/20).The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Before you lies the Special Issue “Personalized Medicine in Epidemics”. As we stated in our call for papers, we were looking for papers which make a novel contribution towards optimizing the personalization of medicine during epidemics. In this context, we aimed to include papers covering all kinds of epidemics, whether big or small, and whether infectious or non-infectious in nature. Personalized medicine is important in all fields of medicine, and all epidemics influence our ability to practice personalized medicine—not only for those suffering from the epidemic disease itself, but also for those with other diseases, which tend to get less attention as a major epidemic unfolds. This broadly inclusive view of the role of personalized medicine during epidemics has led to the inclusion of eleven high quality papers, on a wide range of topics within this Special Issue.Dopazo et al.  review oSticking with diabetes, Leutner et al.  report oBawadi et al.  investigReturning to infectious diseases, Tsai et al.  show thaWu et al.  associatFinally, Hsiao et al.  identifiTogether, these eleven papers demonstrate the wide variety of epidemics in which personalization of medicine is affected. As personalization of medicine is important in all fields of medicine, so are all fields of medicine affected by epidemics. We therefore, after the successful completion of this first Special Issue on “Personalized Medicine in Epidemics”, now open our second Special Issue on this topic “Personalized Medicine in Epidemics 2.0” for submissions.


Dear Editorset al. [I read with interest the article by Epis et al. , reportiRegarding diagnosis of SCD, the authors mentioned that ‘confirmed SCD patients who are anaemic with a suggestive medical history, plus a positive SCD test’ to indicate the methods of diagnosis of SCD. This statement indicated that they did not perform a haemoglobin electrophoresis test, which is the gold standard for diagnosis of SCD. Therefore, they probably included patients with sickle cell trait who typically have a milder form of disease. In the ‘limitations’ section, authors mentioned that there is limited availability of SCD laboratory investigations while in fact the tests are widely available and used routinely in Sudan , 3. FurtIn conclusion, the article has important methodological and ethical limitations. Collaboration will definitely improve patients’ care, which is the main objective of Salam Center and Emergency organization.