*The Experience Sampling Method (ESM):
a real-time Patient-Reported Outcome Measure for symptom assessment in patients with overactive bladder syndrome.*

The overactive bladder syndrome (OAB) is defined by the International
Continence Society (ICS) as a symptom complex of urgency, usually with
frequency and nocturia (awakening at night to void), with (OAB wet) or without
(OAB dry) urinary urgency incontinence. Urgency is the complaint of a sudden
compelling desire to pass urine, which is difficult to defer5. OAB is
clinically diagnosed using the ICS criteria of >=8 micturitions and at least 1
urgency episode per 24 hours.
It is estimated that approximately 16-17% of the adult population of the
Western world is affected by OAB 6,7. Incidence of OAB wet and dry increase by
age 8-10, and because of the worldwide ageing of the population, the number of
adults affected by urinary urgency incontinence (UUI) would increase 11. The
health care costs of OAB are high 12, and work productivity can be
significantly impacted as well 13. In addition, OAB can be associated with
comorbidity and increased mortality14,15. Furthermore, OAB with and without
incontinence has been associated with significantly lower quality of life
scores compared to matched controls without voiding complaints8. It is of
particular interest that OAB does not only affect the patients, but also has an
impact on family members 10.
There is a strong association between OAB and psychiatric comorbidities such as
depression, anxiety and stress 15-19. This association is most likely
bidirectional.16,18,19
The current methods of diagnosis rely on voiding diaries (the sensation-related
bladder diary) and retrospective questionnaires.
Retrospective, self-reported outcomes have important limitations. Firstly,
there is a high risk for recall bias, in which retrospective information
consists of a reconstruction of a few specific moments rather than a reliable
reflection of symptoms over a predefined period of time20-22. Furthermore, it
is well described that memory retrieval is influenced by the individual*s
environment and mental state at the time of recall, known as ecological
bias.20,21 In conclusion, patient experiences about symptoms in the past can be
significantly distorted when retrospectively reported. Furthermore, lack of
patient compliance is an important disturbing factor in recalled assessments.
Studies that employed paper diaries in a population of patients with chronic
somatic pain to measure symptoms resulted in very low patient compliance: only
11% actual compliance, but up to 80% fake compliance was determined, the latter
presumably resulting from filling in diaries after the proscribed time window.23
The Experience Sampling Method (ESM), also referred to as Ecological Momentary
Assessment (EMA), may overcome these limitations. ESM is an electronic
questioning method characterized by random, repeated assessments in the
subject*s current state and environment, for several consecutive days. A
digital device sends out an auditory beep at random moments during the day, to
which subjects have to respond by completing several assessments at the device.
The assessments are identical between the moments 20,21,24. Hereby, ESM offers
the opportunity to reduce the risk for recall bias and to capture symptom
variability over time with taking into account contextual, social and
psychological factors, which might have an impact on symptom reporting.
ESM has already been used in different patient populations with different
disorders, such as; irritable bowel syndrome (IBS) 1, depression 25,26,
Parkinson*s Disease 27 and mental illness in a broad sense.28
ESM has proven to be a viable and novel approach to assess symptoms, affective
states and contextual factors at the level of the individual subject27. It
provides precise, prospective information that may contribute to clinical
practice26 with several distinct advantages over traditionally used
(retrospective) assessment of mental health related phenomena28. OAB shows
fluctuating symptom patterns in which urological complaints might be influenced
by daily life factors as well as psychological and psychiatric comorbidities.
To our knowledge, there are no previous studies on the use of ESM in a
urological patient population. In order to study the performance of ESM in a
population as such there is a need for developing a patient-reported outcome
measure suitable for real-time symptom assessment of urological symptoms, using
the ESM principle. Patient-reported outcome measures (PROMs) are assessment
methods completed by patients, and are meant to capture one or several aspects
of a disease course or health status29. Focus group research in OAB patients
was done for item selection and to evaluate the quality of the PROMs according
to the ESM principle. The outcomes of the focus groups have been discussed in
an expert meeting and a final questionnaire has been constructed, specifically
for the ESM in the urological patient population. Now, this OAB-specific ESM
tool should be tested to see if there is a difference between symptom scores on
ESM and the currently used retrospective reports and SR-BDs. Furthermore
content validity, reliability and the accuracy will be tested to validate the
developed ePRO in OAB patients. Additionally, specific triggers for the onset
of OAB complaints will be objectified, with use of the OAB specific ESM tool.
It will be objectified if there is a direct link between OAB and psychiatric
disorders as depression, anxiety and stress too.

Summarizing, electronic, repeated symptom assessments during daily activities
should assure ecological validity and eliminate recall bias, lead to higher
compliance rates, and capture symptom variability during the day. For these
reasons it is expected that the Experience Sampling Method (ESM) may prove to
be a more objective tool for evaluation and quantification of urgency and other
urological complaints that will overcome the limitations of currently used
retrospective symptom assessment methods in OAB.

This project will be subdivided into three sections:

Part I. Comparison of the ESM vs. SR-BDs and other retrospective questionnaires
in the assessment of urological complaints in OAB such as urgency.
Part II. Validation of new patient-reported outcome measure, based on the
Experience Sampling Method, which will be used in the assessment of urological
symptoms in patients with overactive bladder syndrome.
Part III. Evaluation of provoking and/or alleviating elements in daily life,
that might be of influence on the overactive bladder symptom complex, such as
frequency and urgency.

Part I - Comparison of assessment methods
Primary aim: To compare the ESM to SR-BDs and other retrospective
questionnaires in the assessment of urological complaints in OAB.

Objectives:
1. To compare the ESM to SR-BDs and other retrospective questionnaires in the
assessment of urological complaints in OAB.
Hypothesis: The ESM is more accurate in the assessment of urological complaints
in OAB compared to the current use of SR-BDs and other retrospective
questionnaires (like the OAB-q). A highly significant correlations between the
two assessment methods will be found. Furthermore it is expected that the mean
urgency scores from the ESM will be significantly lower when compared to the
urgency scores from the SR-BDs and retrospective questionnaires.
Additionally it is expected that in the SR-BDs the daily peak of urgency scores
is reported rather than the average level of urgency over the day.

Part II - Validation
Primary aim: To validate and test the reliability of electronic
patient-reported outcome (ePRO) for the evaluation of the complex symptoms and
their potential triggers in OAB patients in day-to-day life with the use of the
Experience Sampling Method.

Objectives:
1. To assess content validity of the developed ePRO.
Hypothesis: We consider content validity of the ePRO adequate since
items were carefully selected based on evidence from qualitative studies.
Furthermore, item relevance was judged by a multidisciplinary panel of experts
in the fields of urology, gastro-enterology, psychiatry and gynaecology as well
as by OAB patients.

2. To assess concurrent validity of the developed ePRO.
Hypothesis: We hypothesize to find good correlations between ESM scores (i.e.
the newly developed ePRO) and *concurrent* instruments (i.e. conventional
retrospective questionnaires), since we purport to measure the same constructs
with both methods. However, ESM measures real-time symptoms whereas our
conventional questionnaires measure retrospectively. Therefore, we do not
expect to find perfect correlation coefficients, i.e. >0.8. Correlation
coefficients between 0.4 and 0.8 are considered appropriate. Correlation
coefficients lower than 0.4 reflect very weak or no correlation between the
methods, which probably means that we are measuring some other construct with
our new ePRO than is measured with the conventional method (current *gold
standard*). On the contrary, correlation coefficients higher than 0.8 reflect
very strong correlations, meaning that we are more or less measuring exactly
the same construct. In this case, there is no rational for replacing the
conventional methods by the new (more intensive) method. For each correlation
coefficient its significance will be checked as well.
3. To assess internal consistency of the developed ePRO.
Hypothesis: We hypothesize that internal consistency of the ePRO will be
moderate to good, since items were based on theoretical constructs as described
in literature. Therefore, we expect to find correlation coefficients
(Cronbach*s α) of >0.6.

4. To assess test-retest reliability of the developed ePRO.
Hypothesis: Since OAB symptoms might fluctuate within the study period, we do
not expect to find perfect test-retest reliability (i.e. test-retest
reliability coefficients close to 1.00). However, it is hypothesized that
symptoms will show certain subject-specific patterns, so consistency between
the first half-week and the second-half week is expected. Therefore, we
hypothesize to find test-retest reliability coefficients around 0.70-0.80.

5. To assess how well the developed ePRO differentiates between OAB and healthy
subjects, by determining the accuracy of the discriminatory model using a
confusion matrix.
Hypothesis: We hypothesize that the accuracy of the ePRO to differentiate
between OAB and healthy subjects will be comparable with ICS criteria, i.e.
moderately to good. There are no studies that examined the sensitivity or
specificity of these criteria. However, since OAB-like symptoms often occur in
healthy subjects we expect that the ePRO might classify some healthy subjects
as OAB (i.e. false positives) resulting in moderate sensitivity and high
specificity.

Part III - Evaluation of influencing factors on urological symptoms
Secondary aim: To evaluate whether specific elements in daily life, i.e.
psychological status or socio-environmental factors, can be found as triggers
for the onset or worsening of urological symptoms in OAB, using the newly
developed ePRO.

1. To objectify specific triggers for the onset of urological complaints in
OAB, using the OAB specific ESM tool.
Hypothesis: By using ESM as an assessment method in OAB, we expect to be able
to objectify specific triggers for the onset of urological complaints. It is
expected that triggers will differ between subsets of participants. Supposed
triggers for urological complaints are negative affective symptoms (i.e.
feeling sad or agitated), uncomfortable situations or unpleasant company.
Furthermore, intake of caffeinated beverages is expected to be related to the
onset of OAB complaints.

The ESM study is a multi-centre, prospective, cross-sectional study in
Maastricht UMC+, Zuyderland Heerlen/Sittard and University Hospital Antwerp..
OAB patients will be recruited at the outpatient Pelvic Care Centre in
Maastricht UMC+, the outpatient clinic Urology at Zuyderland Heerlen/Sittard
and the outpatient clinic Urology at University Hospital Antwerp..
Eligible patients are patients that are referred to the urologist by their
general physician, other medical specialists or other hospitals with a
differential diagnosis of OAB or urinary urgency incontinence. Presently, all
new patients that are seen in the outpatient clinic Urology in the MUMC+, the
outpatient clinic Urology at Zuyderland Heerlen/Sittard and the outpatient
clinic Urology at University Hospital Antwerp, are triaged following the
standard of care on the basis of the guidelines for urinary incontinence, 36,37
Patients that are referred with a differential diagnosis of OAB or urinary
urgency incontinence receive SR-BDs and a HADS questionnaire by post. They are
asked to fill these out and take these with them for their first urologist
appointment.
Since the patients already need to fill out these SR-BDs (and HADS) for their
first regular urologist visit, patients will be contacted by telephone prior to
this first visit to inform them about the study. They will receive written
information (see *E1. Proefpersoon informatie_ESM studie_Patiënten Versie
2.0(18.10.2017)*) about the purpose of the ESM study by post. One week after
receiving this information, a telephone call will follow to answer any
additional questions and to verify whether or not the subject is still
interested in participating. If this is the case, the first visit will be
scheduled at the medical centre to sign the informed consent form (by the
participant as well as the researcher) and to instruct the participant about
the study procedures. No study procedures will be performed until the informed
consent form is signed. After signing the informed consent form they will
receive the login codes of the ESM app and the additional (retrospective)
questionnaires. The SR-BD and HADS will be sent by post, following the usual
way of patient triage of the outpatient clinic Urology MUMC+, the outpatient
clinic Urology at Zuyderland Heerlen/Sittard and the outpatient clinic Urology
at University Hospital Antwerp.
This way of inclusion ensures that patients are not entrusted with filling out
an extra SR-BD for study purposes solely, since they already need to fill these
out following the standard of care for their regular scheduled visit.
An informed consent form (see *E2. IC_ESM_Versie 2.0 (18.10.2017)*) will be
signed by the patients before participation on this prospective study.

Healthy volunteers will be recruited by advertisements on bulletin boards at
Maastricht University Medical Centre, other public bulletin board in Maastricht
and on the website *www.digiprik.nl* (see *E4. Advertentie gezonde
controles_ESM_Versie 2.0 (18.10.2017)*). Persons that are interested in
participating after reading an advertisement are asked to contact the
coordinating investigator via email and will then receive the written patient
information letter and informed consent form E1. Proefpersoon informatie_ESM
studie_Vrijwilligers Versie 2.0(18.10.2017) and E2. IC_ESM_Versie 2.0
(18.10.2017)). One week after receiving this information, a telephone call will
follow to answer any additional questions and to verify whether or not the
subject is still interested in participating. If this is the case, the first
visit will be scheduled at the medical centre to sign the informed consent form
(by the participant as well as the researcher), receive the ESM login codes and
additional retrospective questionnaires, and to instruct the participant about
the study procedures. No study procedures will be performed until the informed
consent form is signed.

Study participation will comprise two appointments with the coordinating
researcher. During the first visit written informed consent will be obtained
and instructions about the study procedures (i.e. ESM and retrospective
questionnaires) will be given. Hereafter, the participant will complete ESM and
the SR-BD during the following week. At the end of the study, the single-time
symptom questionnaires will be completed. At the end of this week another
appointment (*last visit*) follows during which a debriefing session concerning
ESM will take place. In the case of included new patients, this appointment
directly takes place after the patient is seen by the urologist for their
regular outpatient visit. At that moment, all data are collected and study
participation is completed.

Participating in this study does not bring along important risks, since
subjects only have to complete questionnaires and there are no treatments or
investigational products involved. Therefore, this is a low-risk study.
However, completing the PROM several times a day might be quite burdensome and
time-consuming for participants and will intervene with regular daily life.
Completing the SR-BD by measuring the voided volumes with the use of a
measuring cup is sometimes difficult to combine with professional or social
life. However, new patients already need to fill out these SR-BDs for their
first regular urologist visit, so an extra completion of a SR-BD for study
purposes solely will not be needed.
Furthermore, since data are transferred via Internet and partly stored at a
participant*s smartphone, there is a need for securing on an individual*s
privacy. This is described into more detail in section 9.1 *Handling and
storage of data and documents*.
During the study period, subjects will not directly benefit from participation,
since they do not receive any interventional strategy. However, it is possible
that completing the ESM questionnaires makes subjects more aware of their
symptom patterns and possible provoking factors in daily life, which might be
either beneficial or confronting.
All in all, the risks in this study are not disproportional in association with
the benefits. Participants will be informed about the burdens before
participating.