The “Multidisciplinary Approach to the Study of Chronic Pelvic Pain” (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network’s central study and common data elements are described.
The primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as “positive” controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing.
The MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based.
ClinicalTrials.gov identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”. http://clinicaltrials.gov/show/NCT01098279 webcite
Keywords:Urologic chronic pelvic pain syndromes; Interstitial cystitis; Chronic prostatitis; Urine biomarkers; Plasma biomarkers; Non-urologic associated syndromes; Quantitative sensory testing (QST); Neuroimaging
Interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are defined by the hallmark symptom of chronic pain in the region of the pelvis, urogenital floor, or external genitalia, often accompanied by urinary symptoms, such as urinary urgency or frequency [1,2]. The bladder has historically been thought to be the origin of IC/BPS symptoms; whereas the prostate gland has traditionally been believed to be the source of CP/CPPS symptoms. However, this viewpoint has come under recent challenge, in large part from the observation that many IC/BPS and CP/CPPS patients exhibiting symptoms do not have identifiable pathology in these organs [3-5].
The impact and burden of IC/BPS and CP/CPPS are substantial. Patients suffer considerable morbidity resulting in a significant decrease in quality of life for both the patient and his/her partner due to the physical and psychological impact of the condition. In fact, the quality of life of IC patients has been characterized as being worse than that of patients undergoing dialysis . In the U.S., the prevalence of IC/BPS symptoms has been estimated to be 2.7% in women ; whereas the prevalence for analogous symptoms is estimated to be 1.3% in men . Prevalence estimates for CP/CPPS in men vary between 1.8 - 6.4%, depending upon case definitions and screening methods [9,10].
Traditionally, the diagnosis of IC required cystoscopy and pathological findings, although more typically IC/BPS is defined from patient reported symptoms, due to the lack of consistent pathological findings, defined disease phenotypes or biological markers. Similarly, patient symptoms are used to define CP/CPPS. Each of these separate syndromes, however, may in fact represent a group of related conditions that manifest in a similar manner, but have differing etiologies. Based primarily on their somewhat similar symptom profiles , IC/BPS and CP/CPPS are here collectively termed urologic chronic pelvic pain syndromes (UCPPS) (see Table 1 for research definitions used in the MAPP Research Network). As noted in the only published phenotyping system, referred to as UPOINT [11,12], UCPPS patients have significant symptoms across the urinary, psychosocial, organ specific, infection, neurological/systemic and tenderness domains, confirming the heterogenous nature of these syndromes.
Table 1. Terminology used in the MAPP Research Network to described disorders under study
Despite intensive study over the past decade, clinical trials have failed to identify effective therapies, and basic science studies have failed to identify specific pathophysiology for these conditions (for a review of previous research efforts see companion Commentary by Clemens, et al) . Intriguing new clues into the pathophysiology of UCPPS have come from several epidemiological studies revealing shared pathophysiology between UCPPS and other conditions having chronic pain as a cardinal or prominent symptom (e.g., fibromyalgia, irritable bowel syndrome, endometriosis, chronic fatigue syndrome, and vulvodynia) [14-20]. Some of these chronic pain conditions were previously thought to be due to “peripheral” etiologies (i.e., damage or inflammation in the region of the body where the individual was experiencing pain) but are now known to have prominent central nervous system (CNS) contributions (i.e. centralized pain). In light of this new understanding, even the names of some of these conditions have changed, reflecting the fact that peripheral inflammation is not the primary cause of symptoms (e.g., fibrositis became fibromyalgia, spastic colitis became irritable bowel syndrome). In a similar manner, it has been suggested that IC be renamed Bladder Pain Syndrome (BPS), based on the fact that the majority of patients do not have identifiable inflammation or even pathology in the bladder . Collectively, these findings suggest the merits of exploring common underlying CNS pathophysiology (i.e., pain centralization or augmentation) [22-24] rather than continuing the search for a uniform malfunction of a single end organ .
In recognition of these emerging insights and the limitations of previous basic research and clinical studies, the NIDDK established the “Multidisciplinary Approach to the Study of Chronic Pelvic Pain” (MAPP) Research Network to better understand the etiology and treated natural history of UCPPS. This network holds the promise of advancing UCPPS treatment through the identification of clinically relevant patient subgroups potentially requiring distinct interventions . By moving beyond traditional bladder- and prostate-focused investigations toward an innovative multidisciplinary research strategy, the MAPP Research Network is able to more fully investigate the relationship between UCPPS and non-urologic associated syndromes (NUAS), and better define urologic and more systemic contributions to the pathophysiology of these disabling syndromes.
This manuscript describes the approach to clinical phenotyping developed in the MAPP Research Network, with a focus on its central epidemiological study. This integrated research design is highly unique in its evaluation of visceral pain and lower urinary tract symptoms associated with UCPPS, and represents the largest and most detailed characterization of UCPPS to date.
The MAPP Research Network conducts complementary basic, translational, and clinical science studies to investigate questions of clinical relevance, motivated by the view that UCPPS involves substantial central systemic mechanisms. Studies have been designed to advance our understanding of the underlying pathophysiology and etiology, treated natural history, “flare” etiology, risk factors associated with biologic, genetic, and behavioral factors, and the discovery of comprehensive characterizations of patient phenotypes. Another key objective has been to address the relationships between UCPPS and commonly associated non-urologic syndromes (Table 1). The MAPP Network also supports translational studies using UCPPS animal models founded on key clinical criteria and leading hypotheses of UCPPS etiology.
MAPP network organization
The MAPP Research Network consists of six discovery sites (Los Angeles, CA; Chicago, IL; St. Louis, MO; Iowa City, IA, Seattle, WA, and Ann Arbor, MI); several satellite sites (Miami, FL; Birmingham, AL; Palo Alto, CA; Boston, MA; Kingston, Ontario, Canada (CA); a data coordinating core (DCC) in Philadelphia, PA; a tissue analysis and technology core (TATC) in Aurora, CO; a neuro-imaging scan repository and reading center (Los Angeles, CA); an external experts panel (EEP); and NIDDK project scientists (Figure 1).
Figure 1. MAPP Research Network Discovery and Collaborating Sites, Data Coordinating Core (DCC) and the Tissue Analysis and Technology Core (TATC).
MAPP network core functions
The DCC provides biostatistical design and analysis leadership for all studies, serves as the central site for electronic protocol and data management system development, web-based deployment of data capture tools, data acquisition and storage, and promotes network-wide quality assurance across all protocol-specific domains of data. The DCC also provides administrative and project coordination support, including development and maintenance of a public website (http://www.mappnetwork.org/ webcite). The TATC provides a central location for bio-specimen processing, storage, and analysis of blood, urine, and DNA samples. The TATC established and implemented standards for specimen collection, identification, and handling to promote consistent specimen collection procedures. DCC and TATC personnel conducted centralized coordinator training before initiating patient enrollment, with follow-up re-fresher training at periodic Steering Committee meetings. Standardized modular barcoded collection kits with specimen annotation forms for blood, urine, and cheek swab DNA were designed for use at all recruitment sites. The data-sharing model allows sites to enter material requests, specimen collection and shipment information through the DCC portal, with replication in real-time between both DCC and TATC databases (Figure 2). Sites request kits via the DCC portal, following which the TATC sends a shipment of unlinked specimen kits, uniquely identified with a barcode system, to the site, which are individually linked through the DCC portal to a MAPP participant at the time of biospecimen collection. Blood specimens are shipped on the day of collection to the TATC for next day delivery; whereas cheek swab and urine specimens are temporary stored at the collection sites and batch-shipped to the TATC. At-home specimen collection is facilitated by participants, using barcoded collection materials and pre-labeled shipping containers for direct shipping to the TATC. Centralized processing at the TATC ensures standardized processing using best practice standards . Derivative specimen aliquots are barcoded without participant identifying information, allowing for blinded discovery and validation projects. A rigorous series of identity management procedures were implemented between the DCC and TATC to ensure unambiguous links between specimen and participant data. Discovery sites submit specimen requests for research projects to the DCC. Sharing of real-time specimen inventory and annotation data between the TATC and DCC database allows full control by the DCC to match specimens with the required clinical data, and select specimens at the aliquot tube level. After selection by the DCC, a specimen distribution request is transferred to the TATC, triggering shipment to the discovery site. Real-time updates allow the DCC to monitor progress of distribution projects.
Figure 2. Data and Materials Flow Schematic: Left Panel (Data Coordinating Core (DCC) Database) and Right Panel (Tissue Analysis and Technology Core (TATC) Database).
Quantitative Sensory Testing (QST)
QST is a specialized form of assessment that utilizes Pressure Pain Threshold (PPT) to assess pain sensitivity to standardized evoked stimuli. The PPT was determined by using blunt pressure delivered by a 1-cm2 hard-rubber probe to the thumbnail bed of the participant’s non-dominant hand [26-28]. The thumbnail is considered a “neutral site”, both because it is distant from the pain that these individuals are experiencing, and this site has been repeatedly shown to be a good measure of overall “central” pain threshold . Evoked pressure pain, rather than heat pain threshold testing was chosen for MAPP studies for several reasons; first, QST studies have found that pressure pain testing differentiates IC from healthy controls better than does heat stimulation [16,30,31], and secondly, pressure testing was more easily deployed in a standardized manner across multiple sites.
Neuroimaging and functional neurobiology
Neuroimaging and functional neurobiology studies support overall participant characterization, as well as specific trans-MAPP brain imaging studies. These studies were designed to identify differences in brain structure and connectivity [32,33] as well as differences in regional intrinsic oscillation frequencies and resting state connectivity of the brain  between UCPPS patients and control groups. A standardized protocol was developed to acquire structural (grey matter), diffusion tensor imaging; white matter (integrity and connectivity) and resting state images of the brain, as well as functional neurobiology studies across study sites. The magnetic resonance imaging/functional magnetic resonance imaging (MRI/fMRI) data repository for this study was established at the UCLA Center for Neurobiology of Stress (http://pain.med.ucla.edu/ webcite), in close collaboration with UCLA-Laboratory of Neuroimaging (LONI), which has extensive experience in the collection, storage and analysis of large multi-site MRI data sets (loni.usc.edu) .
Biomarker and infectious etiology studies
As a component of the Trans-MAPP EP Study protocol, biological samples (urine, plasma, and cheek swab DNA) were collected at Discovery Sites at baseline (UCPPS patients and control cohorts) and the 6- and 12-month in-clinic office visits (UCPPS patients) (see Table 2 for details on samples collected). In addition, a specialized single-use at-home collection kit was developed for use by UCPPS patients at the time of self-reported flare. These samples were archived at the TATC and distributed to MAPP Network investigators, in conjunction with associated clinical data managed at the DCC, to support integrated studies to identify and characterize UCPPS biological markers (biomarkers) and to examine the potential contributions of infectious agents to UCPPS. The biomarker study uses UCPPS and control plasma and spot-urine collections (Table 2) to assess the utility of previously identified, candidate markers and to identify new markers in a discovery-based approach using proteomics platforms. The infectious etiology study examines VB1 and VB2 (males and females) and VB3 (males) urine samples (Table 2) through advanced 16S deep sequencing methods to assess UCPPS and control microbial profiles and to address hypotheses regarding an infectious basis for symptom development and fluctuations, including symptom flare. Archived DNA samples will be used for targeted epigenetics and genetic investigations.
Table 2. Number of participants (target, enrolled) by cohort, sex (UCPPS: duration of symptoms), and number of participants with biospecimens by type, MRI scans completed and PPT data collected at baseline visit
Flare assessment in UCPPS
Currently it is unknown what triggers a flare of UCPPS symptomatology. Putative risk factors for flares (e.g., dietary factors, physical activity, stress, sexual activities, recent infections) were assessed for participants reporting a flare (limited to three assessments for subjects reporting >3 flares). The same potential flare risk factors were also collected during randomly selected follow-up contacts for participants when not reporting flares, serving as within-person control data. A home collection kit was designed to allow participants to collect urine samples for biomarker and infectious etiology studies at their first reported “flare”. In addition, each participant collected a reference urine sample using the home collection kit at one of the three randomly selected non-flare time points during the first four months. A full set of flare and non-flare biomarker and infectious etiology urine specimens was successfully collected from 188 (44%) of the participants. Another 44 (10%) participants provided only a flare specimen set; whereas 123 (29%) of participants provided only a non-flare specimen set. This reference specimen, together with the urine specimens collected during the in-clinic visits will be analyzed, and compared with the flare specimen, to investigate potential biomarkers and infectious agents that are uniquely present in urine during symptom flares.
Baseline self-report battery characterizing UCPPS and controls
Extensive clinical phenotyping was conducted to characterize UCPPS patients, positive controls and healthy controls at baseline. A description of the self-report battery follows categorized by: General Socio-Demographic and Medical History; Urological Specific Measures; and Non-Urological co-morbidities and diagnostics.
General socio-demographic and medical history
Data on age, sex, race/ethnicity, education, marital status, and income were collected from participant self-report. A directed medical history was gathered on each participant that included co-morbid conditions, early life infection history, concomitant medication use (i.e., name, dose, frequency and route of administration), previous treatments for UCPPS, and family medical history (i.e., history of chronic pain and psychiatric disorders in parents, grandparents, aunts, uncles, siblings, and children). A physical examination included measurement of height, weight and blood pressure as well as abdominal, pelvic, and rectal examinations. Pelvic floor muscle tenderness (yes/no) and suprapubic tenderness (yes/no) were evaluated in each participant. In women, the presence and degree of pelvic organ prolapse was recorded (above or below the hymenal ring). In men, penile exam (circumcised or not), prostate examination (enlarged, irregular, tender) and scrotal examination (varicocele, hydrocele, mass, hernia) findings were recorded.
Urological specific measures
Urological measures were selected purposefully to provide continuity between MAPP and pre-existing literatures on IC/BPS and IC/CPPS. The urological measures thus sought to assess symptoms that have been historically considered relevant to UCPPS with instruments designed specifically for this population (Table 3).
Symptom and health care utilization Questionnaire (SYM-Q) A 12-item questionnaire was developed specifically for this study. All participants completed this questionnaire at baseline and at bi-weekly intervals throughout the 48-week study period. The SYM-Q inquires about (1) pain, urgency, frequency, (2) the presence of non-urological pain symptoms, (3) mood, (4) health care seeking, (5) last menstrual period, and (6) the occurrence of symptom worsening (flares).
Interstitial Cystitis Symptom Index (ICSI) and problem index (ICPI) (ICINDEX) This instrument consists of two 4-item questionnaires. The ICSI quantifies urinary and pain symptoms in patients with IC/BPS, and the ICPI assesses the degree of bother associated with these symptoms .
American Urological Association Symptom Index (AUASI) This validated 8-item questionnaire assesses the severity of voiding symptoms (e.g., frequency, urgency, nocturia, sense of incomplete emptying, intermittency, slow stream, straining to void) and associated bother in either sex .
Brief Flare Risk Factor Questionnaire (BFRFQ) Developed specifically for use in the MAPP Research Network as a means of better understanding flares in UCPPS, the BFRFQ contains 33 items documenting potential causes of flares. It includes questions about diet, physical activity, stress, sexual activity, and infection.
Rand Interstitial Cystitis Epidemiology (RICE) case definition The 5-item RICE case definition questionnaire was designed for epidemiological studies to identify the presence of IC/BPS symptoms in men and women . We used it to identify sub-groups with or without bladder pain and urgency due to pain, pressure, or discomfort.
Genitourinary Pain Index (GUPI) This 9-item instrument was developed by modifying the original NIH-Chronic Prostatitis Symptom Index (CPSI) . Several new items about bladder-specific pain were added, and male gender-specific items were replaced with female-gender specific items for women. The GUPI is applicable to men and women to assess pain symptoms, urinary symptoms, and quality of life as separate sub-scales, and overall as a total score .
Female Sexual Function Index (FSFI) This 19-item scale provides an overall assessment of female sexual functioning over the past 4 weeks, and includes domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain, as well as a total score for sexual dysfunction .
International Index of Erectile Function (IIEF) The IIEF is a multidimensional instrument consisting of 15 items and 5 domains of male sexual function: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Total scores indicate greater levels of sexual dysfunction .
Washington Male sexual function scale (MSFS) This instrument was used in males to rate the severity of the following symptoms: pain with ejaculation, lack of interest in sexual activity, premature ejaculation, and difficulty reaching ejaculation .
Self-Esteem And Relationship questionnaire (SEAR: M & F) The SEAR is a 14-item measure validated to assess psychosocial impact of erectile dysfunction. The measure assesses an overall score, sexual relationship satisfaction, confidence, and self-esteem. The measure was adapted for use in women by omitting the two male-specific items .
Table 3. Baseline phenotyping battery for MAPP: urological self-report questionnaires
Non-urologic co-occurring symptoms and diagnostics
Although pain is experienced locally at a site of discomfort, it is often accompanied by other symptoms that influence pain processing, modulation, and ultimately how it is experienced. Understanding these other influential factors can provide insight into the mechanisms associated with the etiology and maintenance of chronic pain. Thus, the following symptoms and traits were assessed in each participant (Table 4).
History of co-occurring somatic symptoms The Complex Multi-Symptom Inventory (CMSI)  is a 41-item symptom checklist of past year illnesses specific to functional syndromes (e.g., fibromyalgia (FM), chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), vulvodynia (VVD), migraine, and temporomandibular disorders (TMD). The checklist provides a proxy for the presence of these comorbid conditions; whereas the follow–up assessment module uses the standardized diagnostic criteria for each condition . The summed checklist has been interpreted as representing the overall symptom burden from somatic or functional conditions.
Clinical pain The Brief Pain Inventory (BPI) is a 15-item self-report measure that has been validated for use in a wide variety of pain states . The BPI assesses for the presence of pain, pain intensity (i.e., worse, least, average, current), and functional interference from pain. It also catalogues the types of medications being used; the percentage of pain relief obtained from medications, and assesses pain distribution (via a body map). For purposes of the MAPP Research Network, the body map of the BPI was replaced with a more detailed body map used in epidemiological studies to better identify widespread pain by body regions . This more detailed body map was further modified to include larger scale depictions of the pelvic and genital regions. This body map was scored to identify those where pelvic pain was confined to the pelvic region (i.e., pelvic pain only) or was more widespread extending beyond the pelvic region (i.e., pelvic pain and beyond).
Functional status The SF-12 , is a 12-item measure of functional status and generic quality of life. The instrument assesses eight domains of health status: physical functioning, role limitations because of physical problems, bodily pain, general health perceptions, energy/vitality, social functioning, role limitations due to emotional problems, and mental health. It also provides both a composite physical functioning score (PCS) and a mental health composite score (MCS). Higher scores on these measures indicate better functioning within the domain.
Fatigue and sleep disturbance The NIH Patient Reported Outcomes Measurement Information System (PROMIS) developed questionnaires for fatigue and sleep disturbance that can be used across disease conditions. Participants completed the following PROMIS short-forms: Fatigue (7-items) and Sleep Disturbance (8-items) . Higher scores on these measures indicate worse symptomatology.
Cognitive difficulties The Multiple Ability Self-Report Questionnaire (MASQ) assessed the self-perception of having cognitive difficulties . This is a 38-item questionnaire comprised of 5 domains of cognitive concerns: language ability, visio-spatial ability, verbal memory, visual memory, and attention/concentration. Validation studies have found the self-reported cognitive difficulties to correspond to performance-based indices of the same constructs . Higher scores on each scale indicate more problematic perceptions.
Stress Perceived stress was measured using the 10-item Perceived Stress Scale (PSS) . The PSS measures the degree to which situations are perceived as being unpredictable, uncontrollable and overwhelming. Higher scores indicate more stress.
Emotional distress Emotional distress was assessed across several affective domains. Depressive and anxiety-related symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) . The HADS is a 14-item self-report questionnaire developed for use in non-psychiatric settings. This instrument provided both a depressive symptom and anxiety symptom score with validated cut-off scores associated with clinically relevant levels of each affective domain. Anger was assessed with the 8-item anger short form from PROMIS . A potential source of resilience, (i.e., positive affect), was assessed using the Positive and Negative Affect Schedule (PANAS) . This 20-item questionnaire provides both a positive and negative affect score. On each mood measure, higher scores indicate greater problems with mood.
Personality traits Personality was measured using the International Personality Item Pool (IPIP) short form . The IPIP is a public-domain, 120-item instrument that was developed to reflect assessment of five personality domains: extraversion, neuroticism, agreeableness, conscientiousness, and openness to experience. Higher scores indicate greater strength of each personality trait.
Catastrophizing Catastrophizing refers to the perception that pain is overwhelmingly awful and the worst imaginable burden that one can endure. This cognitive perception was assessed using the 6-item Catastrophizing sub-scale from the Coping Strategies Questionnaire (CSQ)  a metric for measuring this construct. Higher scores indicate greater catastrophizing.
Locus of control The Beliefs in Pain Control Questionnaire (BPCQ)  is a 13-item questionnaire designed to evaluate beliefs regarding whether pain is under personal control or under the control of forces external to the patient. Three scales can be derived: (1) Internal scale – measuring beliefs that pain can be personally controlled (2) Powerful Doctors – an external locus of control scale measuring beliefs that pain control is in the hands of powerful others, and (3) Chance Happenings – a second external locus of control scale measuring beliefs that pain is controlled by chance or misfortune. Higher scores on each scale indicate greater strength of each belief.
Early life trauma history The Childhood Traumatic Events Scale (CTES)  is composed of two forms. The first assesses childhood traumatic events that occurred prior to the age of 17. Domains include death of a close family member or friend, parental separation, physical abuse including sexual assault, serious illness, and other. For each question, the age of trauma, perceived intensity of the trauma, and whether or not confiding in others occurred is assessed. The second form is labeled Recent Traumatic Events Scale (RTES). It assesses essentially the same traumatic domains with the exception that the timeframe is within the last 3 years, parental separation is replaced with spouse or significant other separation, and a new category of job change is added. This instrument can be scored to identify the intensity of each type of trauma or intensities can be summed across all traumas. This form is unique in that it also assesses whether the person confided in another individual about the trauma.
Table 4. Baseline phenotyping battery for MAPP: non-urological self-report questionnaires