Good afternoon. I will be presenting on behalf of the Symptoms of Lower Urinary Tract Dysfunction Research Network. I'll provide an overview and our initial findings. The NIDDK has sponsored this research. I'll first provide you some information on the composition of the network and then explain to you how we developed and planned our self-reported measurement work as well as our phenotyping studies. And then I will go over a few of the ideas that we have for our LEARN2 studies. The NIDDK initially developed and funded the LEARN Network with the intention to kind of rejuvenate the lower urinary tract research community. And initially it was funded in 2012 with three clinical sites and a DCC and then in 2013 the addition of three more clinical sites were added. The motivation for LEARN was the premise that patients with lower urinary tract symptoms were not receiving adequate care. And that means that clinically patients present with a wide variety of symptoms. The symptoms are not uniformly related to the lower urinary tract. And findings that are in the etiology of the symptoms may or may not have a source in the lower urinary tract. So to improve the treatment of patients with lower urinary tract symptoms, we need to improve our understanding of the clinically relevant subtypes of LUTs. And we need to then define more empirically based classifications of LUTs and to establish better quality assessments to use for research on finding subtypes of LUTs. So because of the complexity of finding subtypes of LUTs, the Network first decided to make a conceptual framework. And we agreed upon four areas to focus on. The experience of the patients and their symptoms. The organism or the systemic person. The GU organs such as the urethra, the bladder and the pelvic anatomy. And the cellular and molecular factors. There could be many symptoms and many dysfunctions of patients with lower urinary tract symptoms. And they may differ at any one of these levels. Patients may have a variety of different symptoms and may differ at the cellular and molecular level. And therefore, making different subtypes of LUTs. Our next job was to focus on which LUT symptom we would actually be focusing on. And prior research has really focused on the motor aspect. So we wanted to concentrate on the disorders of urinary sensation and its causes. And for the next six years, we developed four interrelated studies under the overarching study, the observational cohort study. These four interrelated studies were our self-reported measure protocols, our neuroimaging and sensory testing protocol, our organ-based pilot study and our biomarker study. We all know that there are many self-reported measurement tools out there. However, strategies on how a tool is developed depends on what the tool is designed to measure. So the goal of LEARN was to get a patient-reported outcome measure that would allow us to find clinically relevant subtypes of LUTs. Therefore, we had to improve our understanding of the patient's experiences by developing a tool and comprise ourselves of a good set of tools that we could then further evaluate and find subtypes. And not only use this tool then as a foundation to adapt it to further then make it as a study, to study endpoints and to use it to monitor patient's progress. So in doing this, developing a tool for finding clinically relevant subtypes of LUTs is very different than developing a tool for using in a clinical trial. The goal was that the self-reported measurement had to then finally discriminate amongst patients with symptoms of LUTs and find subtypes. And the end result was our CASIS questionnaire or what is called the Comprehensive Assessment of Self-Reported Urinary Symptoms. The process of developing the CASIS questionnaire started with reviewing the existing measurement tools that were out there. We then did qualitative work with clinicians and patients with LUTs. We did cognitive pre-testing and we did quantitative analysis of item response. And in developing this tool, focus was really trying to get items that would be able to differentiate upon the different sensations that patients have. The next step was that we wanted to make sure that we were accurately reporting patient's symptoms so that we can find these subtypes. And this was the first study called the RECALL study that ever looked at the RECALL, the accuracy of patients recalling their symptoms at a three-day, seven-day and 28-day period of time. And we found that surprisingly, women were able, of all the LUTs symptoms, women were able to recall their symptoms very well over a 28-day period of time. As I mentioned, we also wanted to focus a lot of our energy in developing studies that would allow us to try to understand the mechanisms of these various subtypes. So the first component of our phenotyping studies was our observational cohort study. And in this study, the goal was to deeply characterize patients. So not only ask them about their symptoms, but also about demographics, non-neurologic factors, health-related quality of life questions, psychosocial, anatomic and clinical factors. The secondary aim was to find subtypes of LUTs using cluster analysis methodology. So the results of the cluster analysis work showed that we were able to identify four distinct symptom-based clusters. And these radar plots pictorially describe the four clusters. And each of the, based on what symptom those patients had and also the severity of their bother. As you can see in cluster F2, those patients had mostly urgency-frequency symptoms and moderate and severe bother. And very little, if any, voiding symptoms, post-micturation or incontinent symptoms. Whereas our cluster 4 had all the LUTs and had severe or moderate bother for all of them. The observation of cohort population was then followed for over a 12-month period of time. And again, the radar plots will describe pictorially the regression of symptoms by the shaded area. There was variability across the clusters in their improvement of symptoms. But as you can see, clusters 2 and 3 had significant reduction of symptoms of their urgency. Where clusters 3 and 4 had significant reduction of the urinary incontinence. As we refine these symptoms-based clusters by adding information of our urodynamic biomarker and neuroimaging information, the goal is that we could end up with cluster-specific treatments which will ultimately help improve our treatment of patients with LUTs. The next part of our study, the next component of our phenotyping study was our neuroimaging and sensory testing study. The premise for this study is the thought that patients with LUTs have very different CNS features and also sensory threshold parameters than patients that don't. So we enrolled patients with LUTs and control patients and had them undergo functional MRI and other sensory testing. And the results of this study are still under analysis. The third component of our phenotyping was our baromarker pilot protocol. The observational cohort study collected biospecimens and this goal of the pilot protocol was to identify appropriate assays that we could then use in a larger cohort. And we were able, while looking at urines and plasma from LUTs patients and controls, we found character proteins in LUTs patients that we will now use and learn to to try to identify and see if there are differences and find a biomarker. The last component of our phenotyping study was our organ based pilot protocol. The organ based protocol was developed and the goal was to look at better functional components that we could explore both in the urethra and bladder. And a very extensive and expansive urodynamic sequence was developed. And the pilot study was just trying to see if in controls will they tolerate such an examination. And it was very successful and so therefore we plan to and learn to be able to recruit both LUTs patients and controls and proceed with that with more of an intense phenotyping study with urodynamics. So over the last six years, the LUT NERC has been able to recruit over 1,000 patients for our observational cohort study. 75,000 biospecimens have been collected and each of our interrelated studies have had recruited enough patients to produce our goals of our research. So what has that done? We've had 18 presentations at professional meetings. This has resulted in 20 publications in peer reviewed journals. The observational cohort study has assembled one of the largest collections of data and biological specimens. And we have, we are developing research products such as our CASIS questionnaire and short form CASIS questionnaire which we will, which will be available to the public to use. So what do we plan to do and learn to? Which actually started this month. We plan to validate the existing symptom based clusters or subtypes. We plan to refine that CASIS questionnaire into a patient reported outcome. Explore those signature proteins that were identified in the pilot study to diagnose subtypes. And to proceed with more deep characterization of the functional components of LUTs by performing our novel studies in the urethra and bladder. And then lastly, definitely we want to integrate all this information from the biomarker, neuroimaging and neurodynamic studies to refine then those symptom based subtypes. So thank you very much for your attention. Thank you. Thank you. Thank you. 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Lower Urinary Tract Dysfunction Research Network

LUT NERC

lower urinary tract symptoms

Comprehensive Assessment of Self-Reported Urinary Symptoms

CASIS questionnaire