PATHOPHYSIOLOGY AND PHENOTYPING OF PELVIC FLOOR DISORDERS
A phenotype is a measurable characteristic of an organism, such as its anatomy, biochemical, neurological or physiological properties, or behavior. Phenotyping is a way to characterize or classify disease expression and severity in an individual using factors such as clinical symptoms, response to therapy, imaging modalities, and anatomic findings. Phenotypes result from the expression of an organism's genes, environmental factors, and the interactions between the two.
One overriding theme crossed all research areas: an accurate understanding of disease mechanisms is critical for advancing disease prevention, developing new treatments, and understanding treatment failure. At present, the identification of causal mechanisms for each of the different pelvic floor disorders is in its infancy, and therefore, our ability to accurately phenotype women is rudimentary. Because of these knowledge gaps, efforts to develop effective prevention and treatments remain empiric. Research is urgently needed to identify mechanisms that contribute to pelvic floor disorders, with heightened recognition that such mechanisms likely may be differentially expressed among women with the same disorder. The panel recommends developing an updated consensus on phenotypes for pelvic floor disorders based on current understanding of symptoms, risk factors, and physical findings. However, the panel also notes the limitations of expert panels and recommends that the current consensus-based approach to phenotyping be submitted to rigorous scientific scrutiny; formal phenotyping studies should be undertaken using techniques such as bioinformatics-driven cluster analysis or other emerging sciences. The panel strongly supports the development of centralized tissue repositories for future research in areas such as genomics, proteomics, and biomarkers. The expectation is that results from such research would then drive refinement of phenotypes, mechanistic research, and, in the long-term, prevention and treatment efforts.
Areas that are likely to be particularly productive include the application of epidemiology, biomechanics, genetics, proteomics, biomarkers, and cellular biology as tools to answer our research questions as well as techniques to improve our understanding of anatomical injury, and mechanisms of age-related deterioration. Research should include women with and without pelvic floor disorders. Standardized validated animal models need to be developed to evaluate tissue, cellular and molecular mechanisms associated with the pathogenesis of pelvic floor disorders and their treatment (including issues such as mesh biocompatibility).
Specific areas of research needed to advance our understanding of the pathophysiology of disease and contributions of biologic and environmental factors include the following:
Recent advances in gene sequencing techniques such as genome-wide association studies (GWAS) allow differences in single nucleotide polymorphisms (SNPs) in the entire human genome to be rapidly detected. By comparing SNP differences across the entire genome between defined phenotypes and controls, putative genes associated with various phenotypes can be identified. Because GWAS requires large sample sizes for both cases and controls, large DNA databanks of carefully phenotyped individuals must be developed. This will enable future mechanistic hypotheses based on genomics findings obtained to be generated. A long-term strategy will be to drill down to the individual gene level where SNP differences are found to affect the function of these identified genes. In this way, novel targeted preventative and treatment interventions (ie, "personalized medicine") can be proposed.
Another recent technologic advance is analysis of the proteosome or the entire protein content of biologic specimens (eg, urine, blood, tissues). By high-throughput analyses of differences in protein expression between pelvic floor disorder (PFD) phenotypes and controls, novel proteins (or biomarkers) can be discovered associated with various PFD phenotypes. Proteosome analyses are reflective of gene products that are variably expressed and extensively modified and consequently, produce more "downstream" information than GWAS genetic analyses as not all genes of interest may be actively transcribed and translated. At this time, however, proteomic technology is less mature than genomics technology. Thus, we recommend that research should focus in the short term on proteomics and biomarker discovery to later generate future mechanistic hypotheses.
The study of factors that affect the health and illness of a population as a basis for the development of rational interventions made in the interest of public health and preventative medicine is an excellent tool to address issues related to the pathogenesis and treatment of pelvic floor disorders. Factors may include specific causal mechanisms such as peripartum events that may contribute to maternal birth injury, lifestyle, environment, occupation, and family history. Epidemiologic data are critical for developing a logical platform on which to base basic science studies.
The individual and collective roles of matrix (fibrillar and nonfibrillar), smooth muscle, and skeletal muscle in the maintenance of pelvic organ support and function must be elucidated. Research is needed to understand the effect of aging, menopause, and structural damage (eg, during childbirth), as well as factors that promote repair following such events (eg, growth factors, oxygenation).
Studies should emphasize the loading conditions, contractile mechanism, timing of contraction/relaxation, and bioactive factors necessary for proper function. Studies should aim to determine in vivo loading conditions during strenuous activity and activities of daily living, active and passive structure-composition-function relationships of load bearing tissues, smooth and striated muscle contractile behaviors, rigorous characterization of vaginal and connective tissue mechanical behavior, the interplay between mechanical demand and biological remodeling of tissue, and the development of focused and experimentally validated computational models describing system-level changes in mechanical demand resulting from a site-specific injury.
Stem Cell Therapy/Regenerative Medicine
The goals of regenerative therapies include reducing or replacing damaged components of the affected tissue or stimulating the matrix production and functional smooth/skeletal muscle components. Our current approaches to the surgical repair of PFDs are anatomical and do not reliably repair function. There is a compelling clinically relevant argument to develop cellular-based therapies designed to restore damaged tissues with muscle-derived stem cells. The 2 main stem cell types that are applicable to our field include adult or tissue stem cells and induced pluripotent cells. Adult stem cells are obtained at any point in the maturation process from the mature fetus to an adult and include those cells derived from skin, brain, bone marrow and cord blood. Induced pluripotent cells are also obtained from adult tissue but are reprogrammed by transduction with retroviruses containing genes that improve growth potential and dedifferentiation. Induced pluripotent cells have generated considerable excitement because of their easy accessibility and potential for complete compatibility because they can be both derived from and used therapeutically in a single host. Potential progress in this area is limited by (1) poor understanding of the pathophysiology of pelvic floor disorders, which in turn limits our ability to define goals clearly, and (2) poor understanding of risks associated with the use of stem cells, particularly relevant in this population of relatively healthy women with a normal life expectancy.
CONSIDER TREATMENT HARMS BEFORE BENEFITS
Another prominent recurrent theme of the research summit was the importance of considering treatment harms before treatment benefits when evaluating new therapies. The 2 current areas of therapeutic development generating this recommendation are surgical innovations and stem cell therapies, but the concept applies to all therapies. Pelvic floor disorders are not life-threatening, and the aim of treatment is to improve quality of life. These indisputable facts make focusing on safety and potential harms of paramount importance. Stem cell therapy and regenerative medicine stand poised to play a role in our field and it is hoped that ultimately this role will be positive and important for our patients. At this time, the panel strongly recommends that research in this area be limited primarily to laboratory and animal research; any human research should be designed to assess safety. Only when adverse outcomes are well understood should research in women be undertaken to explore efficacy of this emerging therapy in our field. The combination of enthusiastic scientists, ambitious clinicians, and industry eager for commercial gain creates a potentially dangerous scenario in which a patient desperate to improve her condition becomes an easy target for unforeseen complications in the event that the technology is introduced too quickly and without good scientific evidence or oversight.
In terms of stem cell therapies, complications as a result of overproduction (neoplasia, organ dysfunction), and migration will not be fully appreciated until more research in humans has been completed. To date, most cell transplantation studies are performed in patients with dismal prognoses (end-stage diabetes, advanced neurodegenerative diseases, spinal cord injury, and cardiac failure) and limited life expectancies. In contrast, women seeking treatment for incontinence and prolapse, quality of life issues, are relatively healthy and most anticipate a normal life expectancy. Thus, in theory, transplanted cells and their potential complications will be present in women with prolapse and incontinence for decades or longer. Moreover, "proof of concept" has been overall disappointing when moving cell-based therapies from animal models in the laboratory to the human patient. It will, therefore, be imperative to follow outcomes in female patients with similar therapies in life-threatening diseases to develop appropriate therapies in our laboratories based on these outcomes and weigh the evidence when it is appropriate to move to clinical trials.
CLINICAL RESEARCH MUST BE EXPANDED TO INCLUDE REAL-WORLD EFFECTIVENESS STUDIES, AS WELL AS RESEARCH ON HEALTH BEHAVIOR, COST-EFFECTIVENESS, AND IMPLEMENTATION SCIENCE
The mechanistic research described above will yield the foundation for a paradigm shift in our field. For example, rather than considering the same therapies for all women with urgency urinary incontinence, a thorough understanding of the mechanism responsible for a specific woman's incontinence (from cerebral cortex abnormalities to bladder mechanoreceptor aberrations to functional disabilities) will pave the road for personalized therapy. However, the pipeline from bench to bedside is a long one, and women, in the meantime, continue to suffer from and seek treatment for PFDs. Research in areas including comparative effectiveness, health behavior, cost-effectiveness, and implementation science is crucial to provide care to women for the foreseeable future. To this end, real progress has been made during the last decade. Increasing numbers of prospective longitudinal cohort studies and comparative effectiveness trials with robust characterizations of participants, multicomponent primary outcome measures, and a priori secondary aims are being designed and executed.
Comparative Effectiveness Research
High-quality randomized trials are necessary to inform decisions about treatment efficacy. Subsequent effectiveness trials should pursue pragmatic designs that maximize external validity. It is also imperative to develop an infrastructure that allows the study of treatment effectiveness (ie, how treatments perform in a more real-world setting). This could take the form of large practice-based networks, registries, or multi-institutional databases and would require developing a system that allows and rewards non-National Institutes of Health (NIH)-funded investigators to contribute patients to ongoing multicenter trials or cohort studies. Long-term follow-up studies for surgical, behavioral, and pharmaceutical therapies are essential. These should last at least 5 years and preferably longer for surgical trials. With changing demographics in the United States, minority and elderly representation must be increased in all areas of research.
As with mechanistic studies, advancement in comparative effectiveness research depends on characterizing phenotypes such that effectiveness in specific subgroups can better be understood. Attention to phenotyping will allow us also to improve our understanding of the role of diagnostic testing and imaging.
Evidence-Based Outcome Measures
Uniform outcome measures should be selected or developed to allow cross-study comparisons and meta-analyses. To select and develop this "bank" of measures, an interdisciplinary team should be convened and should include representatives from traditional federal funding and oversight entities such as NIH and US Food and Drug Administration, as well as a broad representation of other stakeholders including professional societies and patients. Having several uniform measures will allow investigators to select the most appropriate for their research questions and study design. The selection/development team should include representatives from the NIH and US Food and Drug Administration, as well as a broad representation of professional societies and patients. The minimum data set proposed by the NIH Standardization of Terminology for Researchers in Female Pelvic Floor Disorders should be revised to optimize assessment of new surgical techniques as well as the traditional repairs to which they must be compared. The primary outcome measure must evolve beyond purely anatomical outcomes and should distinguish anatomical variation that is and is not associated with patient bother and effect on function. This will require further investigations to define the relationship between anatomy and function. The concept of clinical utility that balances improvement in preexisting symptoms with the development of new symptoms and complications should be explored. A utility measure library for research in this field should be established, including both affected and unaffected individuals and including minority populations.
Management of Surgical Complications and Failures
There is an urgent need for research into how to optimally manage surgical complications, specifically those arising from new surgical technologies (ie, mesh exposure, erosion, or related pain). Data on risk factors for surgical failure and/or complications will help select the best therapy and determine specific subpopulations of patients who may benefit from specific surgical approaches. For example, evidence suggests that implanted grafts can induce a prolonged inflammatory response, which varies between individuals, and is related to undesired outcomes. Research is needed to further define the role of the inflammatory response in graft incorporation and rejection and to inform choice of treatment for individual patients.
The bulk of research to date in this area focuses on urinary incontinence. Research is needed to understand the effect of various nonsurgical therapies, including lifestyle interventions, on pelvic organ prolapse, nocturia, urgency incontinence, and urgency. The role of behavioral and physical therapies on prevention of pelvic floor disorders must be studied. Continence promotion initiatives advocate primary prevention for large populations through public education.
Little attention has been paid to health-related behaviors in women with PFDs. PFD clinicians should foster research collaborations with medical sociologists and behavioral psychologists to better understand predictors of health-related behaviors such as health care seeking, recovery from surgery, adherence to prevention and treatment regimens, choice of treatment, choice of surgical modality, and choice of subspecialist by women with pelvic floor disorders. The best methods for affecting health-related behavior change should be investigated. Research is needed to determine whether modifying health-related behaviors result in improved treatment outcomes.
In addition to investigations about the diagnosis and treatment of pelvic floor disorders, economic and cost-effectiveness analyses are vital to determine whether the health benefits of the interventions are worth the costs. Important measures include estimates of the costs of illness, costs of interventions, health-related quality of life, and cost-effectiveness and/or cost-utility. These additional outcome measures can be used to evaluate the effect of a health condition and/or interventions. These types of analyses provide additional standardized measures by which to compare treatments.
Where feasible, prospective clinical trials should include economic and health-related quality of life measures and should perform within-trial cost-effectiveness or cost-utility analyses using generalizable cost and health-related quality of life measures and current analytic methods.
The fields of simulation modeling and decision analyses should be advanced to estimate health events, costs, and cost-effectiveness. These should include appropriate sensitivity analyses to identify assumptions or variables for which primary data are needed or the threshold where decisions might change.
This emerging area encompasses the scientific study of the uptake of research findings into practice and includes evaluation of uptake in various settings including clinical, community, and public policy contexts. This line of investigation includes research ranging from factors that promote randomized trial uptake in clinical practice to investigations of why established programs (such as behavioral therapies) lose effectiveness over time to why tested therapies exhibit unintended effects when transferred to new settings. Implementation science research is needed to understand how research actually affects clinical care.
Research is needed to determine how practicing surgeons should be taught new surgical technologies that have been shown to have a role based on safety and efficacy. These continuing surgical education programs should use competency-based curriculums and structured assessment of skills. They should be developed, implemented, and regulated by professional bodies free of corporate influence with an ultimate focus of maximizing patient safety.
Add Investigators to the Pipeline
A concerted effort should be made to develop a plan to train and mentor new or junior investigators in the areas highlighted above. In particular, there are exceedingly few investigators in the areas of economic and cost-effectiveness research and implementation science. The panel suggests forming interest groups in these and other areas, coordinated by AUGS, to discuss methodology, research gaps, grant opportunities, and provide mentoring.© 2011 by Wolters Kluwer Health | Lippincott Williams & Wilkins