Lower urinary tract dysfunction is common in both men and women, and the incidence and prevalence increase with advancing age. Symptoms of lower urinary tract dysfunction (LUTD) encompass all urinary symptoms including storage, voiding, incontinence, and post-micturition symptoms. Symptoms of LUTD are highly prevalent and occur in both genders to a similar extent, with 51% of men and 59% of women exhibiting storage symptoms; 26% of men and 20% of women exhibiting voiding symptoms; and 17% of men and 14% of women exhibiting post-micturition symptoms.
The impact and burden of symptoms of LUTD to individuals and to the nation are enormous. Those patients with symptoms of LUTD suffer considerable morbidity resulting in a significant decrease in quality of life for both the patient and his/her partner. According to the results from the NIDDK supported Urologic Disease in America project, the diseases related to the prostate, only one of the organs that may contribute to lower urinary tract symptoms, cost 2.5 billion dollars to the nation in 2000 exclusive of outpatient treatments. A recent analysis of the National Health and Nutrition Examination Survey showed that when urinary incontinence was defined as "urine leakage during physical activity, before reaching the toilet, and during nonphysical activity", the prevalence is 51% in women and 14% in men aged 20 years old or older. When the aging of the population is taken into account, the financial challenge caused by bothersome LUTD is expected to increase dramatically. Treatments for these symptom-based disorders are only modestly effective at best, have significant side-effects, wane in their effect over time, and are costly.
The specific term of "Lower Urinary Tract Symptoms" (LUTS) more commonly relates to infravesical obstructive and bladder irritative symptoms excluding urinary incontinence. The canonical "LUTS" has been traditionally attached to a specific urologic organ, the prostate. In men over the age of 50 LUTS is usually attributed to urinary obstruction caused by an enlarged prostate (e.g., benign prostatic hyperplasia, or BPH). However; recent research suggests that common pathophysiological changes (e.g. inflammation, fibrosis, connective tissue, vascular or neurologic factors) in more than one urologic organ may be responsible for a group of symptoms. Moreover, involvement of non-urological adjacent organs (e.g. colon), remote organs (e.g. brain), other diseases or conditions (e.g. diabetes), medication (e.g. diuretics), or lifestyle factors (e.g. drinking habits) may contribute to the development or modify the severity of lower urinary tract symptom complexes. Thus, the underlying causes for symptoms of LUTD appear more complex than previously appreciated and potentially involve both organ/tissue-specific and more systemic contributions. To address this evolving view, new and novel approaches are needed to better define and categorize different lower urinary tract symptom complexes and identify the underlying cause(s) of observed symptoms and their proportional contribution to overlapping symptom profiles seen in numerous urologic conditions.
Although there are many validated measurement tools used in research evaluating LUTD, they are usually burdensome and do not capture all symptoms related to the lower urinary tract. The American Urological Association symptom score (AUA SS), which was initially intended to objectively quantify the symptoms of BPH patients, is widely used in clinical practice. In addition, it is often used as an endpoint in clinical trials to assess symptom-based clinical improvement in benign lower urinary tract disease. However, objective improvement in symptoms of LUTD following an intervention, does not always correlate with patient expectations, satisfaction and goal achievement, which are critically important for successful management of LUTD. Therefore, overreliance on using the current AUA SS to evaluate all types of symptoms of LUTD limits clinical relevance due to weak correlation with patient satisfaction. This also may be scientifically invalid and impede continued scientific progress in assessing study outcomes relative to symptom bother. Thus, better measurement tools that focuson patient reported outcomes (PRO) are essential to measure early, late, transient, and persistent symptoms of LUTD both in men and women.
Despite years of basic and clinical research, many fundamental questions regarding the etiology and natural history of LUTD remain unanswered. Although epidemiologic studies have uncovered many associations with symptoms of LUTD, there is still a lack of understanding of causality. There is an urgent need for a comprehensive assessment of symptoms of LUTD through phenotyping patients using combined, multidisciplinary approaches, including studies of the natural history of symptoms; structure and function of the lower urinary tract, including contributions of other non-urological factors; interplay between different organs and systems; and biological marker discovery efforts. Special emphasis has to be placed on integrating complimentary epidemiological and basic science approaches to provide a systemic characterization of early symptoms of LUTD, the transient changes, causes and predictors of both progression and response to therapy. Advances and emerging technologies now allow development of better phenotyping methods for individuals with symptomatic conditions. This phenotyping approach should address the long-standing questions in the field and enhance our knowledge allowing for development of improved treatment and prevention strategies.
The goals outlined in this funding initiative were developed in part, based on discussions at the 2011 NIDDK Meeting on Measurement of Urinary Symptoms (MOMUS).
The long term goal of the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) is to construct an interdisciplinary team of researchers to collaboratively 1) develop, test, and ‘fit for purpose’ qualify symptom-based measurement tools to quantitate early, late, transient and persistent symptoms of LUTD in men and women; 2) deep-phenotype a small targeted population from relevant patient cohorts using a multi-disciplinary, integrated approach in order to expand our understanding of the pathophysiological causes of symptoms of LUTD; and 3) to identify methods and collect data and/or samples to find predictors and/or biomarkers of symptom initiation, flare, and progression that may inform strategies to prevent and/or manage disease; and 4) distribute data, research tools and samples to the research community.
The objective of this initial funding opportunity is to solicit applications for Research Sites comprised of teams of investigators equipped with the appropriate knowledge and skills to employ cutting-edge technologies for the development of an item bank founded largely in patient reported outcome (PRO) measures, with accompanying psychometric evaluation, validatity, and cognitive testing for symptoms related to LUTD. The item pools for symptoms of LUTD should be evaluated in large general populations and in well-defined enriched populations. After proper testing for dimensionality, differential item functioning, item fit, other psychometric properties, and proper calibration, a common metric will then be developed for administering via a tailored short form and/or computer adaptive testing (CAT) system.
The first goal is to develop new and moreinclusive, reliable, and generalizable measures of clinical outcomes including, for example, bother, adaptation and exacerbation. Focus groups may be needed to develop key concepts important to patients that are not currently captured . Measurement of PRO is extremely important in clinical trials because quantitative measures such as reduction of post-voiding residual urine or a higher urinary flow rate after an intervention directed toward an organ like prostate or bladder may not translate into an important qualitative benefit to the patient.
An important goal is to develop useful outcome indices that will be adopted for a wide range of future epidemiologic studies and clinical trials. Thus, the applicants should consider that the new PRO measurement tools are expected to substitute for the currently used symptom scoring instruments and serve as a standalone and sufficient measure of outcome as well as a part of a composite index. It is also expected that the new tools would be applicable to a broad population of men and women, the research community, and hopefully professional organizations for the purpose of adapting its use in standard clinical practice. The new PRO measures will be tested populations often under-represented in clinical studies. It is anticipated that the new LUTD symptom measures will later be constructed in different languages and be available for use in international clinical trials and cross cultural research. The new symptoms of LUTD PRO measures will be useful across a broad range of clinical research to assess response to interventions. To achieve this goal, the tool development and clinical testing and validity testing will ultimately need to meet or exceed the scientific and psychometric rigor established by the Patient Reported Outcomes Measurement Information System (PROMIS) network in order to ensure widespread acceptance of the new tools by all interested stakeholders, including ultimately the FDA (http://www.fda.gov/cder/guidance/) and its European counterpart, the European Medicines Agency (EMA) (http://www.ema.europa.eu/).
The second and complementary goal of the LURN is to advance our understanding of the underlying pathophysiology of symptoms of LUTD, the natural history, the causative risk factors for initiation, flares, and progression, and importantly how these collectively contribute to defining patient phenotypes and disease definitions. The individual phenotyping will be an essential part of this effort and should use and validate the developed instruments during the first phase. Studies should define anatomical, physiological and psychological characteristics contributing to underlying pathophysiology to provide comprehensive patient phenotypes with symptoms of LUTD. Patient cohorts comprised of distinct phenotypes may be assembled collaboratively to facilitate the identification of factors important for diagnosis, staging, or to determine response to treatment. The studies are expected to address questions of key clinical relevance and provide findings useful for future clinical prevention and/or intervention strategies.
Finally, collection of data and/or biosamples for identification and validation of predictor and prognostic biomarkers will be an integral aspect of this study. Proposed basic cellular, molecular, and biochemical studies could examine the basis of initiation, exacerbation, remission and progression of symptomatic LUTD at the cellular level using human study materials. These studies could emphasize the identification and validation of new biomarkers that may be used to differentiate the causes of LUTD, predict progression, or response to therapy. Novel and innovative imaging and new technology based in diagnostic and prognostic methods could be utilized to diagnose and differentiate the causes of LUTD. Imaging studies can add our understanding the causes and mechanisms of symptoms related to LUTD initiation, exacerbation, remission and progression. Predictive mathematical and/or computer models should identify those individuals who are likely to progress and require further more invasive therapies.
A Funding Opportunity Announcement information delivery conference call is scheduled for December 20, 2011 between 11:00 a.m. and 12:00 p.m. Eastern Standard Time to describe and explain the objectives, expected structure and functioning of the LURN. Additional conference calls may also be held.
The LURN structure will include one Data Coordinating Center (DCC) and up to 3 Research Sites (RS). The DCC will have a Director with a tract record of experience and success in the past working as a director for major clinical studies. The RSs can have one or multiple Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)). The PD(s)/PI(s) should be scientists with a proven track record of research in their respective fields; one being PRO measurement, and the second being clinical phenotyping of patients with LUTD including both male LUTS, and male and female urinary incontinence.
The Data Coordinating Center (DCC) will provide expertise in the coordination of multi-site research studies and for data analysis. To promote quality control, this shared DCC will serve as the central coordinating center for data acquisition and statistical analyses functions for the multi-site efforts. The DCC will also provide overall administrative support for the LURN including the scheduling and logistics of investigator and External Expert Panel (EEP) meetings and teleconferences; development and maintenance of a LURN website and secure computerized systems for data collection and sharing; preparation of reports and analyses for the projects; and other scientific, administrative, and organizational functions, as required. The DCC will work with the NIDDK Biorepository to coordinate procedures for RS sample collection by widely accepted best practice methods, banking, annotation/blinding, coding, shipping, processing, receipt, and storage of study data that is to be maintained in the Biorepository. The DCC will also be responsible for data acquisition, statistical analyses, and other scientific, administrative, and organizational functions for the LURN investigators-lead projects during the study period. In addition, the DCC will coordinate with the NIDDK Biorepository to prepare the collected data for eventual archiving and distribution.
Applicants for the DCC are expected to establish collaborative relationships with a diverse group of investigators from different disciplines. DCC applications should include evidence that they are able to provide support for different types of data collection, management, analysis, and able to coordinate biosamples collection, banking, coding and shipping to the NIDDK Biorepository.
Applicants for RSs must describe in their application the PD(s)/PI(s) responsible for the PRO measurement tool development and the phenotyping studies. It is expected that the PRO measurement tool development researchers and the phenotyping researchers work in close collaboration. Those researchers responsible for developing the measurement instruments for symptoms of LUTD must have access to the patients. The applications for the PRO measurement tool development and phenotyping studies should both include methods and techniques that can be applicable and usable in other centers. Applicants should be open to work in collaboration with other studies. Final common protocols and research study designs for multi-site studies will be established upon initiation of the program. A sequential approach will be utilized in these research efforts. While preparation for phenotyping studies may be allowed during the early phases; it is anticipated that the PRO measurement tool development will precede the phenotyping efforts. PRO measurement tool development and phenotyping studies will have to be in coordination; and applicants are strongly encouraged to develop strategies on sequential study designs where the new measurement tools can be used and tested in the phenotyping studies. On the other hand, clinical input and access to the patients is essential during the PRO measurement tool development phase. The secondary phase of LURN studies should concentrate on combined use of the PRO measurement tools in selected targeted groups of patients, and development of methods for imaging, novel measurements, biomarkers, and computational analysis. The applicants for RSs should clearly indicate that the PD(s)/PI(s) responsible for the pneotyping efforts have the experience and tract record on individual phenotyping and have large enough practice to recruit patients.
Administration and Meetings
A LURN Steering Committee will be composed of RS PD(s)/PI(s), DCC Director and NIDDK Project Scientist. The Steering Committee will meet regularly in-person and by telephone conference calls to develop and implement the study protocols, review progress of the projects, discuss results, interpret findings, and develop manuscripts for peer reviewed publications. A Chairman for the Steering Committee will be selected by the NIDDK. The Steering Committee will establish an Executive Committee that will be comprised of the Chairman of the Steering Committee, DCC Director, and NIDDK staff. The Executive Committee will make operational decisions for the Steering Committee meetings by means of telephone conference calls in order to advance the conduct of the studies.
The NIDDK will assist the Steering Committee in the development of LURN study protocols; will monitor the progress of all projects, will assist investigators in the analysis and interpretation of data and will aid in preparation of manuscripts for publication.
The NIDDK will establish an External Expert Panel (EEP) to monitor the research efforts and advise the NIDDK and LURN investigators on the progress of the studies. RS and DCC applicants must not suggest potential participants for this committee in their applications.