Estimated prevalence of moderate to severely elevated total homocysteine levels in the United States: A missed opportunity for diagnosis of homocystinuria?

Classical homocystinuria (HCU) is a genetic disorder caused by mutations in the cystathionine beta synthase gene, which results in impaired metabolism of the sulfur-bearing amino acid homocysteine and its accumulation in blood and tissues. Classical HCU can be detected via newborn screening in the United States, but the test is widely acknowledged to miss many patients. While severely elevated homocysteine levels (>100 µmol /L) frequently lead to a classical HCU diagnosis, intermediate levels (>30 to 100 µmol /L), though linked to many of the known complications of HCU, are not always recognized as associated with HCU. We aimed to identify and describe potentially undiagnosed classical HCU patients using a nationally-representative database of administrative claims and laboratory results. We estimated the national prevalence of patients with homocysteine >30 µmol /L, and compared their demographic and clinical characteristics to those of patients with homocysteine levels ≤30 µmol/L. Among 57,580 patients with a homocysteine test result, 1.8% had a value >30 µmol /L. Patients with homocysteine >30 µmol /L were more frequently diagnosed with hypothyroidism (39.2% vs. 20.7%, p < .001) and renal disease (9.7% vs. 5.5%, p < .001), and were more likely to have a prescription for an anxiolytic/antidepressant (44.5% vs. 38.9%), opioid (58.4% vs. 53.1%), steroid (46.4% vs. 42.5%), or thyroid hormone (38.8% vs. 18.8%), compared to patients with homocysteine ≤30 µmol /L (all p < .05). Both groups were equally likely to have a diagnosis of homocystinuria or another disorder of sulfur-bearing amino acid metabolism (3.8% vs. 4.0%, p = .752). The age-adjusted national prevalence of homocysteine >30 µmol /L was estimated at 33,068 (95% CI: 1033 - 35,104). These findings suggest that thousands of people in the US may be living with intermediate to severely elevated homocysteine levels and may require further evaluation for the presence of classical HCU.

Prevalence, characteristics, and costs of diagnosed homocystinuria, elevated homocysteine, and phenylketonuria in the United States: a retrospective claims-based comparison.

BACKGROUND: Classical homocystinuria (HCU), an inborn error of homocysteine metabolism, has previously been estimated to affect approximately 1 in 100,000-200,000 people in the United States (US). HCU is poorly detected by newborn screening, resulting in underestimates of its prevalence. This study compared characteristics, healthcare use and costs, and projected prevalence between patients with diagnosed HCU, elevated total homocysteine (tHcy), and diagnosed phenylketonuria (PKU). METHODS: Patients in the MarketScan® Research Databases were identified with strictly-defined HCU (> 2 diagnoses, including 1 ICD-10), broadly-defined HCU (> 1 ICD-10), elevated tHcy (> 20 µmol/L) without an HCU diagnosis, or > 1 ICD-9/ICD-10 PKU diagnosis during 1/1/2010-12/31/2016 (first qualifying claim = index). Demographics and healthcare utilization and costs per patient per month (PPPM) were compared between all cohorts, frequencies of comorbidities and medications were compared between HCU and elevated tHcy patients, and healthcare provider types were assessed among HCU patients. The prevalence of patients meeting each cohort definition was projected to the United States (US) population. RESULTS: Patients with strictly-defined (N = 2450) and broadly-defined (N = 6613) HCU, and with elevated tHcy (N = 2017), were significantly older than PKU patients (N = 5120) (57 vs. 56 vs. 53 vs. 18 years; p < 0.05). Vitamin D deficiency, hyperlipidemia, folic acid/B vitamins, and lipid-lowering medications, among others, were more common among diagnosed HCU patients vs. those with elevated tHcy (all p < 0.05). Rates of healthcare utilization were generally higher among HCU and elevated tHcy patients, compared to PKU, though total healthcare costs were similar between groups. Most HCU patients (~ 38%) received their index diagnosis from a primary care physician; very few (~ 1%) had any claim from a geneticist during their enrollment. The age-adjusted national prevalence of HCU was projected at 31,162 (95% CI: 30,411 - 31,913; ~ 1 in 10,000 of the US population) using the broad definition. CONCLUSIONS: The actual prevalence of HCU may be > 10 times prior estimates, at 1 in 10,000 in the US, and this study suggests that HCU is not being diagnosed until later in life. Improvements to newborn screening, detection in young children, and physician education regarding HCU among patients may be necessary to alleviate the burden of this genetic disease.

Prevalence of comorbid conditions among adult patients diagnosed with phenylketonuria.

BACKGROUND: Phenylalanine hydroxylase (PAH) deficiency, otherwise known as phenylketonuria (PKU), is an inborn error of metabolism that requires treatment to be initiated in the newborn period and continued throughout life. Due to the challenges of treatment adherence and the resulting cumulative effects of high and labile blood phenylalanine, PKU exerts a significant burden of disease. Retrospective studies using large databases allow for unique perspectives on comorbidities associated with rare diseases. An evaluation of comorbidities across various organ systems is warranted to understand the disease burden in adult patients. OBJECTIVES: The aim of this insurance claim-based observational study was to assess the prevalence of comorbid conditions across various organ systems (e.g. dermatological, renal, respiratory, gastrointestinal, hematological, and others) among adult PKU patients compared with matched controls from the general population. METHODS: This retrospective, case-controlled study selected patients from United States insurance claims databases from 1998 to 2014 using International Classification of Diseases, Ninth Revision (ICD-9) codes for diagnosis of PKU. The date of first diagnosis during the study period was index date and this was not necessarily the first time the patient was diagnosed with PKU. Cases were matched with a 1:5 ratio with general population (non-PKU controls) on age, sex, race, geographic location, duration of time in the database and insurance type. Prevalence and prevalence ratio (PR) calculations for comorbidities across various organ systems among adults (≥20 years old) with PKU were compared with the general population (non-PKU controls). The conditions were selected based on complications associated with PKU and feedback from clinicians treating PKU patients. RESULTS: A total of 3691 PKU patients and 18,455 matched, non-PKU controls were selected, with an average age of 35 years. The mean healthcare costs incurred by the PKU patients during baseline, were approximately 4 times that of the controls ($4141 vs $1283; p < .0001). The prevalence rates of comorbidities across various organ systems during the follow-up period were significantly higher for those with PKU than in the control group. After adjusting for baseline characteristics, the adjusted prevalence ratios (PR) of 15 conditions studied (asthma, alopecia, urticaria, gallbladder disease, rhinitis, esophageal disorders, anemia, overweight, GERD, eczema, renal insufficiency, osteoporosis, gastritis/esophagitis and kidney calculus) were all above PR = 1.24 and significantly higher for the PKU cohort (p ≤ .001). The highest adjusted PR were for renal insufficiency with hypertension (PR [95% CI]: 2.20 [1.60-3.00]; p < .0001) and overweight (PR [95%CI]: 2.06 [1.85-2.30]; p < .0001). CONCLUSIONS: The prevalence of selected comorbidities across several organ systems is significantly higher among PKU patients than for general population controls. Regular screening for common co-morbidities may be warranted as part of PKU management.

Obesity is associated with worse quality of life in women with gynecologic malignancies: an opportunity to improve patient-centered outcomes.

BACKGROUND: The objective of the current study was to evaluate the effect of obesity on pretreatment quality of life (QoL) in gynecologic oncology patients. METHODS: The authors analyzed collected data from an institution-wide cohort study of women with gynecologic cancers enrolled from August 2012 to June 2013. The Functional Assessment of Cancer Therapy-General, site-specific symptom scales, and the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) global mental and physical health tools were administered. Survey results were linked to clinical data abstracted from medical records (demographics and comorbid conditions). Bivariate tests and multivariate linear regression models were used to evaluate factors associated with QoL scores. RESULTS: A total of 182 women with ovarian, uterine, cervical, and vulvar/vaginal cancers were identified; of these, 152 (84%) were assessed before surgery. Mean body mass index was 33.5 kg/m(2) and race included white (120 patients [79%]), black (22 patients [15%]), and other (10 patients [6.5%]). A total of 98 patients (64.5%) were obese (body mass index ≥30). On multivariate analysis, subscales for functional (17 vs 19; P = .04), emotional (16 vs 19; P = .008), and social (22 vs 24; P = .02) well-being as well as overall Functional Assessment of Cancer Therapy-General scores (77 vs 86; P = .002) and Patient-Reported Outcomes Measurement Information System global physical health scores (45 vs 49; P = .003) were found to be significantly lower in obese versus nonobese patients. CONCLUSIONS: Before cancer treatment, obese patients with gynecologic malignancies appear to have worse baseline QoL than their normal-weight counterparts. Emerging models of QoL-based cancer outcome measures may disproportionately affect populations with a high obesity burden. The potential disparate impact of cancer therapy on longitudinal QoL in the obese versus nonobese patients needs to be evaluated.

Correlation of PROMIS scales and clinical measures among chronic obstructive pulmonary disease patients with and without exacerbations.

PURPOSE: The Patient-Reported Outcomes Measurement Information System (PROMIS(®)) initiative was developed to advance the methodology of PROs applicable to chronic diseases. Chronic obstructive pulmonary disease (COPD) is a progressive chronic disease associated with poor health. This study was designed to examine the correlation of PROMIS health-related quality of life (HRQOL) scales and clinical measures among COPD patients. METHODS: A cross-sectional analysis was conducted comparing patients who were stable (n = 100) with those currently experiencing a COPD exacerbation (n = 85). All PROMIS measures for adults available at the time of the study (2008), disease-targeted and other HRQOL instruments, health literacy, percent predicted FEV1, and a 6-min walk distance were assessed when patients were considered clinically stable. RESULTS: Stable COPD patients reported significantly (p ≤ 0.05) better health-related quality of life on PROMIS domains than patients experiencing an exacerbation. PROMIS domain scores were significantly (p ≤ 0.01) correlated with each of legacy measures. Six-min walk scores were most highly correlated with the PROMIS physical function domain scores (r = 0.53) followed by the fatigue (r = -0.26), social (r = 0.24) and to a lesser extent depression (r = -0.23), and anxiety (r = -0.22) domain scores. Percent predicted FEV1 score was significantly associated with PROMIS physical function scores (r = 0.27). CONCLUSION: This study provides support for the validity of the PROMIS measures in COPD patients.

Item-level informant discrepancies between children and their parents on the PROMIS(®) pediatric scales.

OBJECTIVE: The study objective was to describe the individual item-level discrepancies between children ages 8-17 years and their parents for the PROMIS(®) pediatric scales. Contextual effects on item-level informant discrepancies for the pediatric pain interference items were further analyzed conditional on whether the child, the parent, or anyone else in the household experienced chronic pain. METHODS: Parallel pediatric self-report and parent proxy-report items were completed by approximately 300 parent-child dyads depending on form assignment and individual nonresponse. Agreement between parent and child responses to individual items was measured using the polychoric correlation coefficient and weighted κ. The Chi-square test of symmetry was utilized for a comparison of the pattern of parent-child item discrepancies on the response scales, and the differences between the child and parent responses on the 1-5 item response scale are summarized . RESULTS: A continuum of higher item-level parent-child discrepancies was demonstrated starting with peer relationships, anger, anxiety, and depressive symptoms, followed by progressively lower parent-child discrepancies for energy, fatigue, asthma impact, pain interference, upper extremity, and mobility items. Parent-child discrepancies for pain interference items were lower in the context of chronic pain either in the child or in the parent. CONCLUSIONS: Parent-child item-level discrepancies were lower for more objective or visible items than for items measuring internal states or less observable items measuring latent variables such as peer relationships and fatigue. Future research should focus on the child and parent characteristics that influence domain-specific item-level discrepancies, and under what conditions item-level parent-child discrepancies predict child health outcomes.

Trajectory of overall health from self-report and factors contributing to health declines among cancer survivors.

PURPOSE: This study aims to quantify trajectories of overall health pre- and post-diagnosis of cancer, trajectories of overall health among cancer-free individuals, and factors affecting overall health status. METHODS: Overall health status, derived from self-rated health report, of Atherosclerosis Risk in Communities cohort participants diagnosed with incident cancer [lung (n = 400), breast (n = 522), prostate (n = 615), colorectal (n = 303)], and cancer-free participants (n = 11,634) over 19 years was examined. Overall health was evaluated in two ways: (1) overall health was assessed until death or follow-up year 19 (survivorship model) and (2) same as survivorship model except that a self-rated health value of zero was used for assessments after death to follow-up year 19 (cohort model). Mean overall health at discrete times was used to generate overall health trajectories. Differences in repeated measures of overall health were assessed using linear growth models. RESULTS: Overall health trajectories declined dramatically within one-year of cancer diagnosis. Lung, breast, and colorectal cancer were associated with a significant decreased overall health score (ß) compared to the cancer-free group (survivorship model: lung-7.00, breast-3.97, colorectal-2.12; cohort model: lung-7.63, breast-5.07, colorectal-2.30). Other predictors of decreased overall health score included low education, diabetes, cardiovascular disease, and age. CONCLUSIONS: All incident cancer groups had declines in overall health during the first year post-diagnosis, which could be due to cancer diagnosis or intensive treatments. Targeting factors related to overall health declines could improve health outcomes for cancer patients.

PROMIS® Parent Proxy Report Scales for children ages 5-7 years: an item response theory analysis of differential item functioning across age groups.

OBJECTIVE: The objective of the present study is to describe the extension of the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS(®)) pediatric parent proxy-report item banks for parents of children ages 5-7 years, and to investigate differential item functioning (DIF) between the data obtained from parents of 5-7-year-old children with the data obtained from parents of 8-17 year-old children in the original construction of the scales. METHODS: Item response theory (IRT) analyses of DIF were conducted comparing data from the 5-7 age group with data from the established scales for ages 8-17 across 5 generic health domains (physical functioning, pain, fatigue, emotional health, and social health) and asthma. RESULTS: IRT DIF analyses revealed that the majority of the items functioned similarly with responses from parents of younger and older children. A small number of items were removed from the item bank for younger children, and a few items that exhibited statistical DIF were retained in the pools with the caveat that they should not be used in studies that involve comparisons of younger children with older children. CONCLUSIONS: The study confirms that most of the items in the PROMIS parent proxy-report item banks can be used with parents of children ages 5-7. It is anticipated that these new scales will have application for younger pediatric populations when pediatric self-report is not feasible.

Urinary incontinence and health-related quality of life among older Americans with and without cancer: a cross-sectional study.

BACKGROUND: Few studies have investigated the impact of urinary incontinence (UI) on health-related quality of life (HRQOL) among cancer survivors. UI is prevalent in the general population and can be both an indicator of cancer and a side effect of cancer treatment. UI and cancer diagnoses have been associated with decreases in HRQOL. This study evaluates the prevalence of UI and the impact on HRQOL among older cancer survivors. METHODS: The prevalence of UI among cancer survivors (breast, prostate, bladder, colorectal, lung, and endometrial/uterine cancers) and those without cancer was estimated using the SEER-MHOS database. Factors associated with UI were investigated using logistic regression and the impact of UI on SF-36 scores was determined using linear regression. RESULTS: Over 36% of SEER-MHOS beneficiaries without cancer reported UI and higher prevalence was noted among cancer survivors (37%-54% depending on cancer type). History of bladder, breast, endometrial/uterine, or prostate cancer was associated with higher prevalence of UI. UI was independently associated with both lower physical component scores (PCS) (-1.27; 95%CI:-1.34,-1.20) and mental component scores (MCS) (-1.75; 95%CI -1.83, -1.68). A suggested decreasing trend in the prevalence of UI was associated with a longer time since cancer diagnosis. CONCLUSIONS: UI was highly prevalent, especially in bladder, endometrial/uterine, and prostate cancer survivors. Improved recognition of UI risk among cancer survivors will help clinicians better anticipate and mediate the effect of UI on individuals' HRQOL.

Development and psychometric properties of the PROMIS(®) pediatric fatigue item banks.

PURPOSE: This paper reports on the development and psychometric properties of self-reported pediatric fatigue item banks as part of the Patient-Reported Outcomes Measurement Information System (PROMIS). METHODS: Candidate items were developed by using PROMIS qualitative methodology. The resulting 39 items (25 tiredness related and 14 energy related) were field tested in a sample that included 3,048 participants aged 8-17 years. We used confirmatory factor analysis (CFA) to evaluate dimensionality and differential item functioning (DIF) analysis to evaluate parameter stability between genders and by age; we examined residual correlations to evaluate local dependence (LD) among items and estimated the parameters of item response theory (IRT) models. RESULTS: Of 3,048 participants, 48 % were males, 60 % were white, and 23 % had at least one chronic condition. CFA results suggest two moderately correlated factors. Two items were removed due to high LD, and three due to gender-based DIF. Two item banks were calibrated separately using IRT: Tired and (Lack of) Energy, which consisted of 23 and 11 items, respectively; 10- and 8-item short-forms were created. CONCLUSION: The PROMIS assessment of self-reported fatigue in pediatrics includes two item banks: Tired and (Lack of) Energy. Both demonstrated satisfactory psychometric properties and can be used for research settings.

Development of six PROMIS pediatrics proxy-report item banks.

BACKGROUND: Pediatric self-report should be considered the standard for measuring patient reported outcomes (PRO) among children. However, circumstances exist when the child is too young, cognitively impaired, or too ill to complete a PRO instrument and a proxy-report is needed. This paper describes the development process including the proxy cognitive interviews and large-field-test survey methods and sample characteristics employed to produce item parameters for the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric proxy-report item banks. METHODS: The PROMIS pediatric self-report items were converted into proxy-report items before undergoing cognitive interviews. These items covered six domains (physical function, emotional distress, social peer relationships, fatigue, pain interference, and asthma impact). Caregivers (n = 25) of children ages of 5 and 17 years provided qualitative feedback on proxy-report items to assess any major issues with these items. From May 2008 to March 2009, the large-scale survey enrolled children ages 8-17 years to complete the self-report version and caregivers to complete the proxy-report version of the survey (n = 1548 dyads). Caregivers of children ages 5 to 7 years completed the proxy report survey (n = 432). In addition, caregivers completed other proxy instruments, PedsQL™ 4.0 Generic Core Scales Parent Proxy-Report version, PedsQL™ Asthma Module Parent Proxy-Report version, and KIDSCREEN Parent-Proxy-52. RESULTS: Item content was well understood by proxies and did not require item revisions but some proxies clearly noted that determining an answer on behalf of their child was difficult for some items. Dyads and caregivers of children ages 5-17 years old were enrolled in the large-scale testing. The majority were female (85%), married (70%), Caucasian (64%) and had at least a high school education (94%). Approximately 50% had children with a chronic health condition, primarily asthma, which was diagnosed or treated within 6 months prior to theinterview. The PROMIS proxy sample scored similar or better on the other proxy instruments compared to normative samples. CONCLUSIONS: The initial calibration data was provided by a diverse set of caregivers of children with a variety of common chronic illnesses and racial/ethnic backgrounds. The PROMIS pediatric proxy-report item banks include physical function (mobility n = 23; upper extremity n = 29), emotional distress (anxiety n = 15; depressive symptoms n = 14; anger n = 5), social peer relationships (n = 15), fatigue (n = 34), pain interference (n = 13), and asthma impact (n = 17).

PROMIS® Parent Proxy Report Scales: an item response theory analysis of the parent proxy report item banks.

OBJECTIVE: The objective of the present study is to describe the item response theory (IRT) analysis of the National Institutes of Health (NIH) Patient Reported Outcomes Measurement Information System (PROMIS(®)) pediatric parent proxy-report item banks and the measurement properties of the new PROMIS(®) Parent Proxy Report Scales for ages 8-17 years. METHODS: Parent proxy-report items were written to parallel the pediatric self-report items. Test forms containing the items were completed by 1,548 parent-child pairs. CCFA and IRT analyses of scale dimensionality and item local dependence, and IRT analyses of differential item functioning were conducted. RESULTS: Parent proxy-report item banks were developed and IRT parameters are provided. The recommended unidimensional short forms for the PROMIS(®) Parent Proxy Report Scales are item sets that are subsets of the pediatric self-report short forms, setting aside items for which parent responses exhibit local dependence. Parent proxy-report demonstrated moderate to low agreement with pediatric self-report. CONCLUSIONS: The study provides initial calibrations of the PROMIS(®) parent proxy-report item banks and the creation of the PROMIS(®) Parent Proxy-Report Scales. It is anticipated that these new scales will have application for pediatric populations in which pediatric self-report is not feasible.

PROMIS Pediatric Anger Scale: an item response theory analysis.

PURPOSE: The Patient-Reported Outcomes Measurement Information System (PROMIS) aims to develop patient-reported outcome (PROs) instruments for use in clinical research. The PROMIS pediatrics (ages 8-17) project focuses on the development of PROs across several health domains (physical function, pain, fatigue, emotional distress, social role relationships, and asthma symptoms). The objective of the present study was to report on the psychometric properties of the PROMIS Pediatric Anger Scale. METHODS: Participants (n = 759) were recruited from public school settings, hospital-based outpatient, and subspecialty pediatrics clinics. The anger items (k = 10) were administered on one test form. A hierarchical confirmatory factor analytic model (CFA) was conducted to evaluate scale dimensionality and local dependence. Item response theory (IRT) analyses were then used to finalize the item scale and short form. RESULTS: CFA confirmed that the anger items are representative of a unidimensional scale, and items with local dependence were removed, resulting in a six-item short form. The IRT-scaled scores from summed scores and each score's conditional standard error were calculated for the new six-item PROMIS Pediatric Anger Scale. CONCLUSIONS: This study provides initial calibrations of the anger items and creates the PROMIS Pediatric Anger Scale, version 1.0.

Greater Adherence and Persistence with Injectable Dulaglutide Compared with Injectable Semaglutide at 1-Year Follow-up: Data from US Clinical Practice.

PURPOSE: Greater medication adherence and persistence have been associated with improved glycemic control in patients with type 2 diabetes mellitus. This study compared adherence, persistence, and treatment patterns among patients naïve to glucagon-like peptide 1 receptor agonists initiating once-weekly injectable treatment with dulaglutide versus semaglutide over 6-month (6M) and 12-month (12M) follow-up periods. METHODS: This retrospective, observational cohort study used administrative claims data from three IBM MarketScan research databases. Data from adult patients with type 2 diabetes newly initiating treatment with dulaglutide or semaglutide between January 2018 and January 2020 (index date was defined as the earliest fill date), without evidence of glucagon-like peptide 1 receptor agonist use in the 6M baseline period, and with continuous enrollment in the 6M baseline and 6M or 12M follow-up period were included. Dulaglutide initiators were propensity score-matched, in a 1:1 ratio, to semaglutide initiators in each 6M and 12M follow-up cohort (26,284 and 13,837 pairs, respectively). FINDINGS: In the matched cohorts, baseline characteristics were balanced; the mean age was 53 years, and 50% of patients were women. Compared to semaglutide initiators, dulaglutide initiators were more adherent (6M, 63.4% vs 47.8%; 12M, 54.4% vs 43.3%; both, P < 0.0001), more persistent on therapy (6M, 72% vs 62%, 12M, 55.5% vs 45.3%, both, P < 0.001), and had more mean days of persistence (6M, 145 vs 132, 12M, 254.3 vs 220.7; both, P < 0.001). IMPLICATIONS: At both 6M and 12M follow-up, dulaglutide initiators had significantly greater adherence and greater persistence compared with matched semaglutide initiators.

Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction.

OBJECTIVE: • To estimate and predict worldwide and regional prevalence of lower urinary tract symptoms (LUTS), overactive bladder (OAB), urinary incontinence (UI) and LUTS suggestive of bladder outlet obstruction (LUTS/BOO) in 2008, 2013 and 2018 based on current International Continence Society symptom definitions in adults aged ≥20 years. PATIENTS AND METHODS: • Numbers and prevalence of individuals affected by each condition were calculated with an estimation model using gender- and age-stratified prevalence data from the EPIC study along with gender- and age-stratified worldwide and regional population estimates from the US Census Bureau International Data Base. RESULTS: • An estimated 45.2%, 10.7%, 8.2% and 21.5% of the 2008 worldwide population (4.3 billion) was affected by at least one LUTS, OAB, UI and LUTS/BOO, respectively. By 2018, an estimated 2.3 billion individuals will be affected by at least one LUTS (18.4% increase), 546 million by OAB (20.1%), 423 million by UI (21.6%) and 1.1 billion by LUTS/BOO (18.5%). • The regional burden of these conditions is estimated to be greatest in Asia, with numbers of affected individuals expected to increase most in the developing regions of Africa (30.1-31.1% increase across conditions, 2008-2018), South America (20.5-24.7%) and Asia (19.7-24.4%). CONCLUSIONS: • This model suggests that LUTS, OAB, UI and LUTS/BOO are highly prevalent conditions worldwide. Numbers of affected individuals are projected to increase with time, with the greatest increase in burden anticipated in developing regions. • There are important worldwide public-health and clinical management implications to be considered over the next decade to effectively prevent and manage these conditions.

Using the PedsQL™ 3.0 asthma module to obtain scores comparable with those of the PROMIS pediatric asthma impact scale (PAIS).

BACKGROUND: The National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) has developed several scales measuring symptoms and function for use by the clinical research community. One advantage of PROMIS is the ability to link other scales to the PROMIS metric. OBJECTIVES: The objectives of this research are to provide evidence of validity for one of the PROMIS measures, the Pediatric Asthma Impact Scale (PAIS), and to link the PedsQL™ Asthma Symptoms Scale with the metric of the PAIS. METHODS: Descriptive statistics were computed describing the relationships among scores on the PAIS, the PedsQL™ Asthma Symptoms, Treatment, Worry, and Communication Scales, and the DISABKIDS Asthma Impact and Worry Scales for approximately 300 children ages 8-17. A novel linkage method based on item response theory (IRT), calibrated projection, was used to link scores on the PedsQL™ Asthma Symptoms Scale with the metric of the PAIS. RESULTS: The PAIS exhibited strong convergent validity with the PedsQL™ Asthma Symptoms Scale, and less strong relations with the other five scales. The linkage system uses scores on the PedsQL™ Asthma Symptoms Scale to produce relatively precise score estimates on the metric of the PAIS. CONCLUSIONS: Results of this study provide evidence for the validity of the PAIS, and a method to use scores on the PedsQL™ Asthma Symptoms Scale to estimate scores on the metric of the PAIS, in partial fulfillment of the PROMIS goal to provide a lingua franca for health-related quality of life.

Randomized Clinical Trial or Real-World Evidence: How Historical Events, Public Demand, and the Resulting Laws and Regulations Shaped the Body of Medical Evidence.

SUMMARY: The signing of the 21st Centuries Cures Act in 2016 was a confirmational step in a long journey toward an understood use and need for real-world evidence (RWE), even though the Food and Drug Administration (FDA) had the legislative authority to accept RWE since 1962 to demonstrate efficacy. The 21st Century Cures Act, as well as the subsequent FDA guidance published in 2017 and other supporting guidance, documents that since are opening the doors for the clinical and research community. They specifically allow for labeling changes and indication expansion based on RWE. The legislative discussion of efficacy requirements started in the late 1950s, when evidence of effectiveness was not required in the United States before the marketing of a drug or medical device, and calls for the real-world comparative effectiveness research were being made by Senator Estes Kefauver. When the thalidomide tragedy stuck, Congress and the Kennedy Administration rushed to pass a new law to require that drugs be "effective in use." The regulations subsequently drafted by the FDA to enforce the law often required placebo-controlled, randomized clinical trials (RCTs). In the 1980s, some started to label the RCT as the gold standard for medical evidence. The use of real-world data for new indication approval was not specifically prohibited by the 1962 law, but the new 2016 law sent a clear mandate to FDA, requiring the agency to review new forms of evidence such as RWE.

Methodologies for Validation of Diagnoses in Real-World Data: BONES-A Case Study.

SUMMARY: The accuracy of any claim-based study is dependent on the quality of real-world coding of the condition of interest. This retrospective, administrative claims analysis presents a method for using a real-world data source to evaluate the accuracy of coding for nonunion of a fifth metatarsal fracture. Patients 21-80 years old with a diagnosis of a fifth metatarsal fracture between January 1, 2016, and October 31, 2016, and a nonunion of the fifth metatarsal fracture within the next 9 months were identified in the MarketScan Databases. Patient health care claims in the 12 months after the nonunion diagnosis were examined for health care encounters and pharmaceutical treatments considered indicative of treatment for nonunion, such as claims for bone growth stimulation or a second claim with a diagnosis of nonunion. Of the 230 patients who had at least one health care encounter attributable to a nonunion of the fifth metatarsal, 95.2% had at least one subsequent health care encounter confirming nonunion diagnosis. The mean number of supporting health care claims was 5.8, and the mean time between nonunion and first confirmatory claim was 33 days. This analysis demonstrated a method for evaluating the quality of coding for a specific condition when a traditional medical chart comparison is not feasible.

Real-World Evidence: A Primer.

SUMMARY: The insights that real-world data (RWD) can provide, beyond what can be learned within the traditional clinical trial setting, have gained enormous traction in recent years. RWD, which are increasingly available and accessible, can further our understanding of disease, disease progression, and safety and effectiveness of treatments with the speed and accuracy required by the health care environment and patients today. Over the decades since RWD were first recognized, innovation has evolved to take real-world research beyond finding ways to identify, store, and analyze large volumes of data. The research community has developed strong methods to address challenges of using RWD and as a result has increased the acceptance of RWD in research, practice, and policy. Historic concerns about RWD relate to data quality, privacy, and transparency; however, new tools, methods, and approaches mitigate these challenges and expand the utility of RWD to new applications. Specific guidelines for RWD use have been developed and published by numerous groups, including regulatory authorities. These and other efforts have shown that the more RWD are used and understood and the more the tools for handling it are refined, the more useful it will be.