Abstract
Introduction
Few studies have investigated time estimation of daily activities in patients with mental illness. Therefore, we conducted a preliminary study to extract the characteristics of time estimation in patients with schizophrenia.
Method
We conducted an investigation using the Questionnaire of Time Experience in Daily Activities in patients with schizophrenia and healthy controls. We compared the results between schizophrenia patients and healthy controls using t-tests.
Results
Thirty-four people participated in each group. T-tests showed significantly shorter length of time answers in the schizophrenia group for question 4, (“How long does it take you to go out after waking up in the morning?”). For question 5 (“When you have to take a bus, how long before departure time do you arrive at the bus stop?”) and question 6 (“You have an appointment with your friend. How long beforehand do you arrive at the appointed place?”), the answers of the schizophrenia group were significantly longer than the healthy controls.
Conclusion
Time estimations of some daily activities of patients with schizophrenia were significantly different from those of healthy controls. This study will support the next phase of psychometric testing of the Questionnaire of Time Experience in Daily Activities, after which the results will applicable to practice.
Introduction
When occupational therapists work with clients to help improve their daily lives, we often use items related to time-use to concretely evaluate their daily lives or occupational balance, as well as the quantity of activities performed. For example, the Occupational Questionnaire (Smith et al., 1986) and the time-use diary are two of the most popular assessments and there have been many useful studies regarding occupational therapy practice using these tools. People with a serious mental illness (SMI) such as schizophrenia have been reported to have different time-use in daily living from healthy people. In previous studies using a time-use diary, people with SMI were reported to spend a lot of time on passive activities and “doing nothing” (Hunt and McKay, 2015). Also, people with SMI had fewer social situations in which they connected to other people than people without SMI (Cella et al., 2016; Minato and Zemke, 2004). Lexén and Bejerholm (2018) suggested a relationship between occupational engagement and cognitive functioning. In practice, occupational therapists help clients change their lifestyle or occupation based on the results of assessments. Also, occupational therapists usually estimate clients’ use of time in daily life together with them, and aim to help them live a more active and meaningful life. One example of a structured occupational therapy intervention for people living in the community with SMI is Action Over Inertia (Krupa et al., 2010), which uses a time-use log (diary) to assess clients’ occupational balance. The results of the assessment are shared with occupational therapists and clients, and are also used for goal-setting and monitoring. In such situations, we usually share the same time estimation and time perception with our clients in our practice.
On the other hand, time estimation by people with schizophrenia has been reported to be different from that of healthy people. For example, some previous studies have investigated the time experience of patients with schizophrenia from a psychopathology point of view. Stanghellini et al. (2016) compared the clinical files of patients with schizophrenia with those of patients with depression by means of consensual qualitative research. Their results showed some abnormalities in how time is experienced by patients with schizophrenia, such as the disruption of time flow. Some patients indicated that they felt like “the world was like a series of photographs” or that they experienced déjà vu/vecu, meaning that they experience places, people and situations as already seen and news as already heard. Other patients had premonitions about themselves in which they felt like something was going to happen to them or that they were going to do something. Moreover, their results showed disturbed experience of the speed of time (accelerated time experience, decelerated time experience or both) and discrepancies in the meaning of time experience such as significant differences in time experience from before illness onset, or loss of commonsense time references. Surprisingly, Manschreck et al. (2000) reported that around 25–30% of hospitalized psychiatric patients in chronic care facilities experience age disorientation, misstating their age by at least 5 years.
Those abnormal time experiences and differences in time estimation could influence occupational therapy because our practices are usually constructed using the time measured by the clock or by experiences that clients are familiar with. Occupational therapists will have difficulty in their practice if clients have different time estimations for activities in their daily lives than they expect. Also, if there is no common time reference for activities, it is difficult to create activity plans with clients smoothly.
Basic research on short term experiences (from seconds to minutes) in patients with schizophrenia shows they have impaired time perception and a lower ability to correctly judge temporal order than healthy subjects. Also, difficulties measuring the precise duration of acoustic stimuli are related to cognitive functions such as attention or working memory (Gómez et al., 2014). Viewed in this light, in occupational therapy practice, we need to manage clients’ lifestyles with consideration of the differences in their time estimations because such differences could influence shared practices and how goals are set with clients. To realize this, we have to evaluate clients’ time estimation by determining their characteristics of time estimation and helping them manage their lives in a way that best suits them.
Stanghellini et al. (2016) previously suggested the importance of clarifying the characteristics of time experience of people with schizophrenia and sharing this information among medical staff and patients since it gives a more realistic picture of the client’s daily life and contributes to support aimed at recovery. However, previous studies on the time estimations of patients with schizophrenia are limited to short periods of time (for example minutes) or are based on time-use diaries (for example 24 hours). Therefore, the time estimations of patients with schizophrenia regarding daily living activities remain unclear. Since patients with schizophrenia are often treated by occupational therapists, we need to clarify the characteristics of time estimations of daily activities and make use of the information in occupational therapy.
Therefore, the purpose of this study was to extract the characteristics of time estimations of daily living activities in patients with schizophrenia. We hypothesized that people with schizophrenia would have different time estimations for daily activities compared with people without schizophrenia. We investigated time estimations of daily living activities using a relatively simple questionnaire, and compared the results of patients with chronic schizophrenia with those of people without schizophrenia (healthy controls). Additionally, we examined the characteristics of time estimation in patients with chronic schizophrenia and compared the results between inpatients and patients living in the community. The results of this preliminary study will help occupational therapists promote occupational engagement and management of clients’ daily lives.
Method
Design
We carried out a self-administered questionnaire investigation on the time experiences of daily activities in both patients with schizophrenia and healthy controls. We then compared the responses of the two groups and extracted characteristics of time experiences of daily activities in patients with schizophrenia. Moreover, we analyzed the relationships between these characteristics and patients’ symptoms and background information.
Participants
The participants in this study consisted of two groups: people with schizophrenia (schizophrenia group) and people without schizophrenia (healthy controls). Taking into consideration both the analysis plan and the purpose of this preliminary study, we set the sample size as about 30 participants for each group.
Schizophrenia group
Participants were recruited from 10 psychiatry hospitals and two day-service centers where the authors were working in Aichi Prefecture, Japan. The inclusion criteria were as follows: (a) over 20 years old; (b) diagnosed with schizophrenia by the attending psychiatrist according to the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5); (c) inpatients with psychiatry hospital or day-service use; (d) receiving occupational therapy and (e) able to understand and answer the questionnaire by themselves. Patients with other psychiatry diagnoses complicated with schizophrenia were excluded. The authors of this study, who were all occupational therapists, selected participants of occupational therapy groups or day-service programs, focusing on patients with chronic schizophrenia at their institutions, and informed them about this study. The reason that we recruited these patients was because we thought there would be less influence of symptoms and less burden of participation in other research than in acute patients. Moreover, the authors, who were occupational therapists in charge of their clients, took the following into consideration when recruiting participants based on their occupational therapy practice: their clients had interpersonal functions and social skills that they could adapt to supportive groups conducted in general psychiatry hospitals or day-service centers in Japan with specialized staff such as occupational therapists; and their clients did not have obvious problems with time estimations or life skills related to time-use in their daily living (for example difficulty reading a clock, obvious memory problems or higher brain dysfunctions that caused disturbance in their daily lives). In other words, when recruiting participants, we confirmed that they did not have features that were obviously different from the majority of patients with chronic schizophrenia who use general hospitals and day-service centers in Japan.
Healthy controls
Participants in this group were over 20 years old and had no history of psychiatric disorder. They were recruited from staff of the authors’ affiliated psychiatry hospitals. We displayed a poster requesting cooperation in our research in the affiliated hospitals, and those who offered to cooperate were given full details of the study. The poster indicated “no history of mental illnesses” as an inclusion criterion; however, we did not confirm the absence of mental illness among healthy controls. We regarded them as healthy people based on the condition of having certain paid work.
All procedures were approved by the Research Ethics Committee of the Graduate School of Medicine, Nagoya University, Japan (authorization number: 2017-0090), and all the participants provided written and verbal informed consent to participate.
Measures
Background information and measurements
Age and sex were collected in both groups as background information. In addition, the following information was collected in the schizophrenia group: (a) dosage of antipsychotics (chlorpromazine equivalent (mg)); (b) age at onset of schizophrenia; (c) total duration of hospitalization (inpatients) or number of day care use days (day-service users) and (d) duration of hospitalization (inpatients) or number of day-service use days (day-service users) for the current treatment.
The severity of symptoms of schizophrenia was evaluated with the Positive and Negative Syndrome Scale (PANSS). PANSS is a 30-item measure of symptom severity for patients with schizophrenia (Kay et al., 1987). We chose the three-factor model consisting of a positive symptom scale (seven items), negative symptom scale (seven items) and a general psychopathology scale (16 items). Each item requires a symptom to be scored on a seven-point scale ranging from 1 (not present) to 7 (extremely severe). The reliability and validity of the Japanese version of PANSS have been confirmed (Kay et al., 1991).
Time Estimation in Daily Activities Questionnaire (Q-TEDA)
In this study, we aimed to clarify the characteristics of time estimation in people with schizophrenia; however, we could not find an appropriate assessment tool. In occupational therapy, although we evaluate clients’ activities of daily living with tools such as the Assessment Motor and Process Skills (Pan and Fisher, 1994), most of these tools focus on functional capacity and do not mention time estimation. Therefore, in this study, we developed and used the Time Estimation in Daily Activities Questionnaire (Q-TEDA). Q-TEDA was administered to both schizophrenia patients and healthy controls. Q-TEDA is a self-administered questionnaire on the time experience of seven daily activities. Participants answered questions on the length of time it takes to do each of the seven daily activities. Q-TEDA was developed by the authors for this study following the procedures described below.
Preliminary investigation for the development of Q-TEDA
First, the 15 authors of this article, who were occupational therapists, discussed daily activities performed most frequently by Japanese people and extracted 40 daily activities along with the approximate length of time required to complete each activity. All authors had clinical experience in providing occupational therapy to patients with schizophrenia.
In the process of selecting activities from the initial 40 daily activities for use in the Q-TEDA, the authors carefully extracted those that satisfied the following conditions: (a) familiar and general for most people (basically the same regardless of frequency of experience); (b) detailed information and context about the activity is not required; (c) the purpose of the activity is simple and easy to understand and (d) the length of time needed to complete each activity described in the questionnaire is over 1 minute. As a result, we extracted 20 activities for use in the Q-TEDA. All procedures for selecting these activities were conducted by the members of our research team.
Second, we conducted a preliminary investigation in 65 healthy persons with the same inclusion criteria as the healthy controls. The answers were analyzed in minutes for each activity. We calculated the mean, standard deviation and coefficient of variation for each activity. Because a coefficient of variation (standard deviation/mean) of over 0.6 indicated that the length of the activity varied depending on the person, questions with a coefficient of variation of over 0.6 were excluded. Additionally, many participants felt it was difficult to answer the following two questions: “How long do you think is a suitable bath time?” and “How long of a walk do you think is suitable?” Therefore, these two questions were also excluded. Finally, as a result of the preliminarily investigation, the following seven questions were selected for the Q-TEDA:
How long does it take to hard boil an egg? How long does it take to make toast? How long do you need for lunch? How long does it take you to go out after waking up in the morning? When you have to take a bus, how long before departure time do you arrive at the bus stop? You have an appointment with your friend. How long beforehand do you arrive at the appointed place? In the middle of the summer, you hang your laundry on the handrail of the veranda. How long does it take to dry?
Additionally, the order of questions in the actual Q-TEDA was randomized for each participant to avoid the order of the questions influencing the answers.
Administration of Q-TEDA
Participants in both groups were given the following instructions: “Please provide the length of time for each activity. You can use any units, for example, hour, minute, second.” In the schizophrenia group, one of the authors stood with the participants and assisted them in answering the questions. Participants in the schizophrenia group could ask questions that did not influence their responses (for example, “What kind of unit should I use?” “Do I need to write my name?” etc.), but the instructors did not answer questions related to the actual Q-TEDA responses (for example, “How long do you think?” or “How large of an egg does this question mean?”). In the healthy controls, the participants completed the questionnaire by themselves.
Analyses
The length of time given by the participants for the Q-TEDA questions was converted into minutes, and means and standard deviations were calculated. We then compared the length of time between the schizophrenia group and healthy controls using a t-test (Welch-Aspin test). Additionally, we conducted subordinate comparisons with one-way analysis of variance (ANOVA) among three groups: healthy controls and the schizophrenia group divided into two sub-groups (inpatients and day-service users who lived in the community). Tukey’s test was used as a post-hoc test after one-way ANOVA.
Results
Participants
Table 1 shows the mean age, sex (both groups), hospitalization days, total hospitalization days, period of day-service use, total period of day-service use, sum dosage of antipsychotics and PANSS scores (in the schizophrenia group). Mean age was not significantly different between the two groups. Healthy controls were not involved in the preliminary investigation for the development of the Q-TEDA.
Basic information in both groups.
*p < 0.05, **p < 0.01.
SD: standard deviation; PANSS: Positive and Negative Syndrome Scale.
aScores between the two groups were compared using one-way ANOVA and the t-test (Welch-Aspin test).
Additionally, we compared age, age at onset of schizophrenia (years), sum dosage of antipsychotics (chlorpromazine equivalent (mg)) and PANSS scores between patients in the schizophrenia sub-groups. The scores of all three PANSS domains (positive symptoms scale, negative symptom scale and general psychopathology scale) were significantly higher in the inpatients than in the day-service users.
Q-TEDA
The comparison of Q-TEDA results between the schizophrenia group and healthy controls is shown in Table 2. T-tests showed significantly shorter length of time answers in the schizophrenia group for question 4 (“How long does it take you to go out after waking up in the morning?”). For question 5 (“When you have to take a bus, how long before departure time do you arrive at the bus stop?”) and question 6 (“You have an appointment with your friend. How long beforehand do you arrive at the appointed place?”), the answers of the schizophrenia group were significantly longer than the healthy controls.
Comparison of Q-TEDA between the schizophrenia group and healthy controls.
*p < 0.05, **p < 0.01.
All values are in minutes.
SD: standard deviation; Q-TEDA: Questionnaire of Time Experience in Activities of Daily Living.
aScores between the two groups were compared using a t-test (Welch-Aspin Test).
Table 3 shows the comparison of Q-TEDA results among the schizophrenia sub-groups and healthy controls. The answer for question 5 (“When you have to take a bus, how long before departure time do you arrive at the bus stop?”) was significantly longer in the schizophrenia sub-groups. The answers in the inpatient group were significantly longer than in the day-service users’ group and healthy controls.
Comparison of Q-TEDA among sub-groups in schizophrenia group and healthy control.
All values are in minutes. *p<0.05, **p<0.01.
SD: standard deviation; Q-TEDA: Questionnaire of Time Experience in Activities of Daily Living; SZ-in: inpatients group in schizophrenia; SZ-day: day-service users’ group in schizophrenia; HC: healthy control.
Scores between the three groups were compared using one-way ANOVA.
Discussion and implications
Based on previous studies, we hypothesized that participants with schizophrenia would have different time estimations for daily activities compared with healthy people, and tested that hypothesis in the present study. As a result, we found significant differences regarding some activities, and those results are described below.
Time estimation requires social cognition
Participants in the schizophrenia group answered with longer times than healthy controls for question 5 (“When you have to take a bus, how long before departure time do you arrive at the bus stop?”) and question 6 (“You have an appointment with your friend. How long beforehand do you arrive at the appointed place?”). More specifically, participants in the schizophrenia group answered that they would arrive earlier than the healthy controls. In Q-TEDA, participants are required to understand the situations presented in each question and to imagine themselves in that situation. After that process, they estimate the time in their answers. Questions 5 and 6, which had longer times in the schizophrenia group than the healthy control group, required adjustment depending on other things or people. Two factors are important for this adjustment.
The first factor was time estimation regarding social context. For example, in question 5, participants decided the time based on the social context, which was how early or late the bus would generally arrive in Japan. Similarly, in question 6, the appropriate time for meeting friends has implications for appropriate behavior in Japanese culture (not to be late and not to arrive too early). People with schizophrenia were reported to have difficulty understanding social context (Green et al., 2015). Generally, these problems were conceptualized as a set of mental operations underlying social interactions, and are therefore related to the ability to interpret and predict the behavior of others. García et al. (2018) defined the functional areas that constitute the domain of social cognition, including, as a minimum, the theory of mind, sensory perception, social perception, and attributional bias, and pointed out the impairment of these areas. In this study, similarly, deficits of social cognition may have influenced time estimations in social contexts.
The second factor was difficulty in performing dual tasks. When imagining dual tasks, participants must estimate the time for both themselves and another person’s activities, and adjust accordingly. In question 5, participants were required to estimate time based on how soon a bus would come. In this case, question 5 actually included two questions: “How soon/late do you think the bus will come to the bus station based on the schedule?” and “How long before/after the time you imagine the bus coming do you usually arrive at the bus station?” Problems in dual tasks were reported in previous reports on people with schizophrenia (Li et al., 2019). Additionally, working memory was reported to be necessary in dual tasks. People with schizophrenia are said to have difficulties in verbal working memory, and those difficulties were also reported to influence their daily lives (Fujii and Wylie, 2003; Green et al., 2000).
Questions 5 and 6, which included both time estimation regarding social context and dual tasks, might have presented difficulties for participants with schizophrenia. Moreover, question 6 required supposing someone else’s actions and generalizing an appropriate time estimation. Therefore, participants in the schizophrenia group might have required better understanding and higher cognitive function. Shohamy et al. (2010) reported that people with schizophrenia had selective alteration in the ability to flexibly generalize past experience toward novel learning environments. Such cognitive characteristics may have also influenced the results of this study.
We investigated the results of questions 5 and 6 in post-hoc analyses. Namely, responses in both sub-groups were significantly longer in the schizophrenia group than in healthy controls in question 6, whereas in question 5, responses of day-service users with schizophrenia were not significantly different than healthy controls. Based on these findings, it seems that the schizophrenia group had difficulty in answering question 6.
In this study, however, we did not conduct cognitive function testing. Therefore, we cannot determine whether the participants had cognitive impairment or clarify the relationships between the study results and the participants’ cognitive function. On the other hand, Heaton et al. (1994) reported that decline in cognitive abilities is present in most patients with schizophrenia. Additionally, Bozikas and Andreou (2011) reported that, in their review of longitudinal studies, chronic patients with schizophrenia had certain cognitive impairments although most of them did not proceed to psychosis. Based on these previous studies, we supposed that participants with schizophrenia in this study had at least some cognitive impairment. Looking at the participants’ responses as social coping skills in light of their difficulties with time estimation might lead to more conclusive results. Namely, they might arrive at the appointed place or bus stop earlier in order to successfully perform the task because it is difficult to judge the appropriate time. In order to clarify these possibilities, social functioning must be evaluated in a future study.
Interesting results were also revealed for question 7 because the participants needed to imagine a general veranda and how long laundry generally takes to dry in the summer in Japan. Although the participants needed to make generalizations, time estimation was limited to only one activity. Therefore, question 7 might have been easier to answer than questions 5 and 6. However, the SD of question 7 in the schizophrenia group was large. We could not determine the factors influencing this result, but question 7 required longer time estimation than other questions because the activity itself requires a longer time than the activities in other questions. This was thought to be the reason for the large SD in the schizophrenia group. In the future, we need to investigate the characteristics of time estimation in activities indicated to take a longer time by patients with schizophrenia.
Influence of lack of activities actually performed in daily life
Question 4 (“How long does it take you to go out after waking up in the morning?”) showed a significant difference between the two groups. In this question, participants in the schizophrenia group answered with a shorter length of time than the healthy controls. We inferred that this difference showed actual differences in the length of time to prepare to go out. This indicated there were differences between the two groups in the kinds of activities that participants always perform before going out. Generally, healthy people take care of their appearance, and have routines such as eating and cleaning before going out. On the other hand, people with schizophrenia have been reported to neglect self-care (Häfner et al., 1999); therefore, their time estimation for question 4 was shorter than that of the healthy controls.
Also, several previous studies reported that people with schizophrenia had fewer activities of daily living and difficulties with constructing routines (Eklund et al., 2009; Lipskaya-Velikovsky et al., 2016). Moreover, they do not have as many opportunities for social interaction and participation in social activities that require preparation (Gorostiaga et al., 2017). Therefore, we believe it is possible that the schizophrenia group had fewer activities to prepare for than the healthy controls. In this study, we could not draw this conclusion with certainty because we did not investigate the number or type of activities actually performed before going out. In a future study, we hope to consider the relationships between time estimation and activities that are actually performed before going out.
Suggestions for occupational therapy practice
Occupational therapists often use memory and working memory when helping clients manage their time-use. We are required to consider impairment in function or disabilities in order to provide appropriate support. However, this consideration was often limited to actual points to give attention to in our practice. In other words, differences in time estimation of daily activities are often not investigated. This study offers the novel finding that people with schizophrenia have difficulty with time estimations in daily activities because of impaired cognitive function and coping skills.
The results of this study showed that people with schizophrenia had different strategies of time estimation in simple daily situations such as appointments that allowed them to judge social contexts with impaired cognitive functions. Occupational therapists should keep this in mind as a premise of our practice and show sensitivity toward clients’ difficulties with daily activities.
Occupational therapists specialize in engagement activities, analysis and reflecting on our experiences with our clients. Such specialties enable us to approach our clients’ time-use, including time estimation, in a direct manner. Clients’ sharing their time concepts with people in the community may allow for meaningful participation in community activities, and may aid measurement of the effectiveness of occupational therapy practice.
As mentioned previously, few studies have reported on time-use in people with schizophrenia from the viewpoint of time estimation of daily activities. The present study used Q-TEDA to investigate time estimation; however, the validity and reliability of Q-TEDA have not been confirmed. Therefore, our results are preliminary and not applicable to practice at this stage. Additionally, we could not conduct analyses on the relationship between symptoms in the schizophrenia group and time estimations. Although this was a preliminary study, the results are expected to support the next phase of psychometric testing of Q-TEDA, and after its validity and reliability have been confirmed, the results will be applicable to practice. Further studies will be needed in the future.
Limitations
First, we should mention the validity and reliability of Q-TEDA. Because this was an exploratory study that aimed to extract the general characteristics of time estimation regarding daily activities in patients with schizophrenia, we did not confirm the validity and reliability of Q-TEDA, and this is a limitation of our results. However, we plan to conduct future studies to better understand time estimation in patients with schizophrenia making use of the results of this study. Moreover, we selected activities commonly performed in Japan. Therefore, Q-TEDA may not adapt well to other countries or cultures. If similar studies are conducted in other countries, it is recommended that activities be selected to match the study area and culture.
Second, the results of this study did not reveal the characteristics of time estimation in all people with schizophrenia. As previously mentioned in the Method section, we recruited participants with chronic schizophrenia. However, we could not control for all background situations and characteristics, and therefore, the participants were not uniform. Moreover, the study participants were not randomly selected and the persons who selected the participants were also the study evaluators. Therefore, the study was not blind. We could only assess the participants’ characteristics through the seven Q-TEDA questions and our results are considered preliminary.
Third, we did not collect information on cognitive functioning or the ability to perform daily activities. More information on this would help clarify our results.
In future studies, we hope to reveal the relationship between the characteristics of time estimation of daily living activities in patients with schizophrenia and their wellbeing, and would like to develop effective interventions for occupational therapy.
Conclusion
We conducted a questionnaire survey on time estimation of daily activities in people with chronic schizophrenia. The results showed that people with schizophrenia had difficulties in estimating time for activities that required social cognitive function (for example working memory, generalizations and predictions to cope with estimations), and they estimated longer times than the healthy controls. On the other hand, participants with schizophrenia estimated shorter times for some activities, reflecting their lack of engagement in daily activities. Based on this result, the following strategies are recommended for occupational therapists’ practice: (a) show sensitivity toward difficulties that clients experience due to cognitive impairment and provide appropriate support; and (b) try to help expand clients’ occupational engagement through activities in their actual daily life. Further development of the Q-TEDA is needed to provide accurate assessment and to confirm the results before they can be used to inform practice.
Key findings
In some daily activities, participants with schizophrenia estimated time differently from healthy controls. Time estimates for daily activities might have been affected by social cognition or lack of performance in participants with schizophrenia.
What the study has added
This study revealed new characteristics of time estimation for daily activities in patients with schizophrenia and suggested new strategies to help occupational therapists understand their clients and perform accurate assessments.
Footnotes
Acknowledgments
The authors are deeply grateful to all the participants for completing the questionnaire. We are grateful to Dr. Kunifumi Suzuki for useful discussions in the early stages of this work. This research was conducted under the name “Project Time-use” by “Annex Studio,” which is a research team of occupational therapists at Nagoya University. We would like to offer special thanks to Akari Hukui, Arisa Goto, Hiroyuki Yamamoto, Ichiro Kutsuna, Kanako Sakakibara, Eri Yoshihara, Takuya Kenmochi, Tatsuya Omori, Yoko Yamamura, and Yoshiro Nakagawa for their involvement in this project.
Research ethics
All procedures were approved by the Research Ethics Committee of the Graduate School of Medicine, Nagoya University, Japan (authorization number: 2017-0090).
Declaration of conflicting interests
The authors confirm that there is no conflict of interest.
Funding
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Contributorship
All authors contributed to formulating the research question and designing the methodology. Aiko Hoshino applied for ethical approval. Tatsumi Asakura, Kilchoon Cho, Natsumi Murata, Aki Kito, Urara Kato, Tomohiro Kogata and Masashi Kawamura carried out the data collection, data extraction, and synthesis of results. All authors contributed to interpreting the data. Aiko Hoshino wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version.
