key: cord-0866389-n7eo56to authors: Mank, Arenda; van Maurik, Ingrid S.; Bakker, Els D.; van de Glind, Esther M. M.; Jönsson, Linus; Kramberger, Milica G.; Novak, Petr; Diaz, Ana; Gove, Dianne; Scheltens, Philip; van der Flier, Wiesje M.; Visser, Leonie N. C. title: Identifying relevant outcomes in the progression of Alzheimer's disease; what do patients and care partners want to know about prognosis? date: 2021-08-20 journal: Alzheimers Dement (N Y) DOI: 10.1002/trc2.12189 sha: 849c02d4ff5b06445fad4abbb96918e08a9ef0c8 doc_id: 866389 cord_uid: n7eo56to BACKGROUND: Prognostic studies in the context of Alzheimer's disease (AD) mainly predicted time to dementia. However, it is questionable whether onset of dementia is the most relevant outcome along the AD disease trajectory from the perspective of patients and their care partners. Therefore, we aimed to identify the most relevant outcomes from the viewpoint of patients and care partners. METHODS: We used a two‐step, mixed‐methods approach. As a first step we conducted four focus groups in the Netherlands to elicit a comprehensive list of outcomes considered important by patients (n = 12) and care partners (n = 14) in the prognosis of AD. The focus groups resulted in a list of 59 items, divided into five categories. Next, in an online European survey, we asked participants (n = 232; 99 patients, 133 care partners) to rate the importance of all 59 items (5‐point Likert scale). As participants were likely to rate a large number of outcomes as “important” (4) or “very important” (5), we subsequently asked them to select the three items they considered most important. RESULTS: The top‐10 lists of items most frequently mentioned as “most important” by patients and care partners were merged into one core outcome list, comprising 13 items. Both patients and care partners selected outcomes from the category “cognition” most often, followed by items in the categories “functioning and dependency” and “physical health.” No items from the category “behavior and neuropsychiatry” and “social environment” ended up in our core list of relevant outcomes. CONCLUSION: We identified a core list of outcomes relevant to patients and care partner, and found that prognostic information related to cognitive decline, dependency, and physical health are considered most relevant by both patients and their care partners. 1. Systematic review: The literature shows that most patients and their care partners desire prognostic information. However, prognostic studies mainly attempted to predict progression to dementia, and it is questionable whether this is the most relevant outcome from a patient's perspective. The few available studies that focused on patient-relevant outcomes were based on interviews in small samples. Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by cognitive decline and dementia. 1 Dementia is in fact a late stage of this disease that takes decades to develop. Pre-dementia stages of AD include preclinical AD, which may express as subjective cognitive decline (SCD) and mild cognitive impairment (MCI). 1 Advances in biomarker-based diagnostic testing allow for an AD diagnosis in pre-dementia stages. 2 However, the question asked immediately after "doctor, what is wrong with me?" is "what can I expect?" 3 The establishment of an individual prognosis is still challenging due to the high variability in disease course and phenotypic manifestation. 1 In addition, it is not fully known which information patients and care partners would value most about their course of the disease. Until now, prognostic studies mainly attempted to predict progression to dementia. While the syndrome diagnosis of dementia is an important endpoint in research, it may be rather an arbitrary point along the entire disease trajectory from the perspective of patients and care partners. 4, 5 Which endpoints are most relevant to patients has not yet been thoroughly assessed. In addition, factors that are important for patients to know about the future may differ from those of care partners. As care partners have a significant role when making (dementia) care-related decisions, it is important to identify both patient-and care partner-relevant outcomes in the prognosis of AD. 6, 7 In addition, it can be debated whether the data we collect at memory clinics during routine follow-up cover the prognostic information most relevant to patients and care partners. There is increasing inter-est in so-called patient-reported outcomes (PROs). 8 These include aspects such as (health-related) quality of life, activities of daily living, and interpersonal functioning from the perspective of patients and care partners, which may be missed during our current, routine checkups. Some existing outcome instruments, such as TOPICS-MDS, are already based on patient report. 9,10 These outcome sets however have mostly been developed without consulting patients and caregivers about what is relevant to them. A few former studies that took into account patients' perspectives mostly focused on specific disease outcomes or on experiences with specific treatments. 11, 12 The few available studies that focused on relevant outcomes from the perspective of patients were based on interviews in small samples. 13, 14 In the current study, taking the viewpoints of patients and care partners as the starting point, we aimed to identify outcomes in the disease course of AD relevant to patients and care partners from multiple European countries. In this mixed-method, multicenter study, we used a two-step approach with four focus groups followed by an online survey that was distributed in multiple European countries. Written informed consent was obtained from participants of the focus groups and digital informed consent was obtained from participants of the online survey. Local boards of the medical ethics committee reviewed and approved this study. We took on a qualitative, bottom-up approach, using focus groups to elicit a comprehensive list of patient-and care partner-relevant outcomes in the progression of AD to serve as input for the online survey (step 2). We conducted four focus groups. For each question, participants were first given 5 minutes to write their answers on individual sticky notes. Then, one by one participants were asked to read out loud and explain one of the outcomes they had written down. We collected and placed the sticky notes on large paper sheets, broadly clustering them into categories. In subsequent rounds, the participants expanded these lists with outcomes that had not yet been mentioned. After all outcomes had been read out loud and broadly categorized, participants were asked if they could think of any additional outcomes of relevance to them, which were then added. Audio recordings were made of all focus groups, and the sticky notes on the paper sheets were also saved. One author (AM) transcribed the audiotaped focus groups using intelligent verbatim transcription. A second author (EDB) checked the transcripts for completeness. The transcripts were analyzed in MAXQDA software 15 using a process of inductive and deductive thematic analysis (directed content analysis). One author (AM) generated a "start list" of codes based on literature, prior to coding. Subsequently, two authors (AM and LNCV) coded the transcripts independently, adding, adjusting, and categorizing the codes based on the transcripts and the answers from the sticky notes. Afterward, they compared and discussed the differences in coding until consensus was reached. After the fourth focus groups, data saturation was achieved, that is, no new outcomes were identified based on the data from the fourth focus group compared to the previous three focus groups. The final list consisted of 60 outcomes, which were subdivided into five categories. The item "How long am I able to decide whether I want euthanasia?" is only relevant in the Netherlands, because euthanasia is not legally permitted in the other European countries, and the final list used in the European survey thus included 59 items. Subsequently, we used a quantitative, online European survey to determine the most relevant items among the outcomes identified in the focus groups. Participants were recruited via multiple routes. We recruited patients and care partners through memory clinics in the Netherlands, Slovenia, and Slovakia, who were then sent a link to the online survey. In addition, the online survey was sent to members (patients and care partners) of the dementia association Demensförbundet in Sweden. Finally, Alzheimer Europe sent a link to the online survey to members (patients and care partners) of its European Working group of People with Dementia. Alzheimer Europe also invited three of its member associations (i.e., national AD associations) to share this link with members of other similar English-speaking national working groups of people with dementia and care partners. Patients were eligible to participate if they had a diagnosis of SCD, MCI, or mild dementia. Because we were interested in outcomes that participants want to know at the beginning of the disease process, severe dementia was not our target group. Care partners were eligible if they were a relative or loved one involved in caring for someone with a diagnosis of dementia, MCI, or SCD. Care partners were not eligible if they were younger than 18 years old. The survey was created in the online survey tool Survalyzer. 16 . Participants also had the option to add additional missing items. As we anticipated that participants would rank many items as (very) important, we subsequently provided them with the items that they rated as "important" or "very important" and asked them to select the three most important items. This stepped approach facilitated the identification of the most relevant items out of the long list of 59 items that resulted from the focus groups. Data was analyzed using version 22.0 of SPSS for Windows. Frequencies and percentages were calculated, resulting in two lists of the 10 items most frequently rated as most relevant by patients and care partners, respectively. We assessed concordance of these two lists between patients and care partners and subsequently compiled a final list of important items merging the top-10 lists of both patients and care partners. We compared the frequency of patients and care partners who selected at least one item as important from the category using a chi-squared test (see Appendix A in supporting information). In total, 12 patients and 14 care partners participated in the focus The supporting information provides an overview of the list of 59 outcomes, ordered by five major categories. This category included outcomes such as learning, recognizing loved ones, planning, and organizing. The following quote is a concrete example of an AD dementia patient who wants to know how the memory symptoms will progress. Notes. The top-10 lists of items most frequently mentioned as most important by patients and care partners were quite concordant, as seven items (70%) were selected by both groups. We merged the seven matching items and the six non-matching items into a core outcome list of 13 most important items as shown in Table 2 . The majority (9 items) of these 13 items is part of the category "cognition," followed by three items in the category "functioning and dependency" and one item in the category "physical health." There were no items from the category "behavior and neuropsychiatry" and "social environment" in the core outcome list. In this pan-European study, we identified a core list with outcomes relevant to patients and care partners in the disease trajectory of AD. stressful, yet our results show that they highly value a prognosis in terms of cognitive outcomes. Patients and care partners are keen to know about the (expected) course of the cognitive outcomes. 17 The current study underlines that we should bridge the gap between cognitive test scores and daily functioning, by making an effort to translate numerical cognitive test results to cognitive outcomes such as mentioned in this study, that is, better reflecting problems with cognition as experienced in daily life. Contrary to our expectation, outcomes from the category "behavior and neuropsychiatry," such as anxiety and apathy, were not often selected by our participants as most important. This finding is in correspondence with results from a previous study, reporting that anxiety and depressive symptoms were not highly prioritized by patients with MCI and their care partners. 11 Nonetheless, behavioral and psychological symptoms are highly prevalent across the entire spectrum of AD, with 96% of the patients showing at least one symptom. 18, 19 Former studies reported that these symptoms were associated with increased risk of institutionalization, difficulties in daily functioning, and caregiver burden. 20, 21 We could speculate that symptoms from the category "behavior and neuropsychiatry" may be more relevant at a later stage, or that patients and care partners may not have realized that these symptoms are related to AD. Alternatively, these symptoms may not be the most striking aspect of managing AD in everyday life, and this could be different in other types of dementia such as dementia with Lewy bodies or frontotemporal dementia, in which behavioral and psychological signs and symptoms are more in the foreground. 22, 23 More research is needed regarding the causes of these symptoms, to better understand and explain their relevance. We observed large variability in the importance rating of individual items, as 33 out of the list of 59 were rated as "most important" by at least one patient or caregiver. When scrutinizing the individual items, some showed some overlap with other items from the same category. For example, the items "How long am I able to recognize my family and friends?" and "When do I no longer recognize anyone?" from the category cognition showed resemblance as they both focused on the ability to recognize others. Nevertheless, on a category level, it was clear that most patients and care partners identified items related to cognitive decline and functional dependence as most important. In view of To our knowledge, this is the first study that has investigated outcomes of relevance to patients and care partners in the disease trajectory of AD (AD dementia, MCI, and SCD) in multiple European countries, using a mixed-methods approach. A former review reported comparable results in relevant outcomes of patients with MCI or AD and their care partners and health-care providers. 24 This review identified some outcomes mentioned in our study, for example, memory, mental health, activities of daily living, and maintenance of identity. Outcomes that we did not replicate are eating behaviors, apathy, and self-efficacy in the ability to manage memory impairment. In addition, a recent qual- itative study examined what matters most to patients and care partners across the AD continuum, by means of interviews only. 25 They also observed that memory (e.g., forgetting friends/family) was reported as one of the most challenging issues by the majority of the participants. In addition, they reported that the impact of AD varies across the disease-severity spectrum. Emotional impact (e.g., more frustrated) and social impacts (e.g., decreased social activities) were most commonly reported in the early stages of AD. However, care partners of patients with mild to severe AD reported impact on their own daily responsibilities as most important. One of the strengths of our study is the two-stepp, mixed-methods approach, whereby we first used a qualitative bottom-up strategy to generate a comprehensive list of outcomes, and then a quantitative approach to provide a selection of most important outcomes from the perspectives of a large sample of patients and care partners. Also, we included participants from 13 different European countries, which is a very heterogonous representation of European countries, which also greatly enhances generalizability. Among the potential limitations is our use of an online survey, which may have led to an underrepresen- 13 and behavior changes 13,28 as relevant. These did not, however, end up in our core outcome list from the perspec-tive of patients and care partners. This would suggest that important outcomes from the perspective of health-care professionals are additionally relevant and could also be taken into account when investigating PROs in AD studies. Of note, seven (7.1%) patients and three (2.3%) care partners in our study reported that they did not want to know anything about the progression of the symptoms. Therefore, it is important to adopt a process of shared decision-making in memory clinics, 29 in which patients, care partners, and clinician decide together which prognostic information about the course of AD is most relevant. To follow patients more efficiently, we could make more use of online opportunities, and this has particularly become relevant in the current times with COVID-19-related regulations that hamper physical visits. We will therefore incorporate our core outcome list in a largescale online data-collection of PROs, supplemented with outcomes that are deemed relevant from the perspective of the professionals (e.g., quality of life and behavior changes). In our online data collection, in addition to questionnaires on quality of life and activities of daily living, we include questions about social environment, and patients' ability to participate in conversations, to recognize loved ones, and to keep up hobbies. Some outcomes identified in our study are too abstract or otherwise impossible to inquire about by means of a questionnaire (e.g., how long am I able to convey what I want to say?). Still, acknowledging these uncertainties and the impossibility to adequately answer these questions in a conversation with the clinician might help them cope. 30 In conclusion, this study resulted in a comprehensive core list of 13 outcomes in the AD trajectory relevant to both patients and care partners. These outcomes can be incorporated in patient care and research, for example, via online survey. Integration of these outcomes into a disease progression model can help to provide patients and care partners with personalized information on prognosis of AD. This study was evaluated on ethical grounds and approved by the local boards of the Medical Ethics Committee (Amsterdam UMC (approval no.2019.282), Karolinska Institutet Stockholm, University Medical Centre Ljubjana, and Institute of Neuroimmunology AD center Slovakia). All participants provided informed consent. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. The authors declare that they have no competing interests. AM, LNCV, WMvdF designed the study. AM, EDB, EMMG, LJ, MGK, PN, AD, DG collected the data. AM, LNCV, EDB conducted the data analysis. AM, LNCV, WMvdF interpreted the data and drafted the article. All authors revised the manuscript. AM had full access to all data in the study. LNCV and WMF were responsible for study supervision. Alzheimer's disease Learning biomarker models for progression estimation of alzheimer's disease Clinicians' views on conversations and shared decision making in diagnostic testing for Alzheimer's disease: the ABIDE project Willingness-to-pay for predictive tests with no immediate treatment implications: a survey of US residents Public attitudes about genetic testing for Alzheimer's disease Family caregivers of people with dementia. Dialogues Caregiver burden in Alzheimer disease: cross-sectional and longitudinal patient correlates Patient-reported outcomes to support medical product labeling claims: fDA perspective. Value Health Development of a patient-reported outcome instrument to assess complex activities of daily living and interpersonal functioning in persons with mild cognitive impairment: the qualitative research phase Priority of treatment outcomes for caregivers and patients with mild cognitive impairment: preliminary analyses Understanding the relative importance of preserving functional abilities in Alzheimer's disease in the United States and Germany Which medical and social decision topics are important after early diagnosis of Alzheimer's Disease from the perspectives of people with Alzheimer's Disease, spouses and professionals? Caregivers in China: knowledge of mild cognitive impairment MAXQDA 12, software for Qualitative Data Analasis Survalyzer to survey & analyze Utrecht Neuropsychological testing: helpful or harmful? Clustering of behavioural and psychological symptoms in dementia (BPSD): a European Alzheimer's disease consortium (EADC) study Clinical features and diagnosis of Alzheimer disease. UpToDate Predicting caregiver burden and depression in Alzheimer's disease Patient and caregiver characteristics and nursing home placement in patients with dementia Frontotemporal lobar degeneration: demographic characteristics of 353 patients Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium What outcomes are important to patients with mild cognitive impairment or Alzheimer's disease, their caregivers, and health-care professionals? A systematic review Assessing what matters most to patients with or at risk for Alzheimer's and care partners: a qualitative study evaluating symptoms, impacts, and outcomes Biomarker-based prognosis for people with mild cognitive impairment (ABIDE): a modelling study Assessing attitudes and behaviours surrounding Alzheimer's disease in Europe: key findings of the Important Perspectives on Alzheimer's Care and Treatment (IMPACT) survey Living with and caring for patients with Alzheimer's disease in nursing homes Diagnostic dilemmas in Alzheimer's disease: room for shared decision making Communicating uncertainties when disclosing diagnostic test results for (Alzheimer's) dementia in the memory clinic: the ABIDE project SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Mank A, van Maurik IS Alzheimer's disease; what do patients and care partners want to know about prognosis? Alzheimer's Dement