Real-world effectiveness of elexacaftor/tezacaftor/ivacaftor on the burden of illness in adolescents and adults with cystic fibrosis.

Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) aged ≥2 years. Here, we describe results from an observational study assessing change in burden of illness following initiating ELX/TEZ/IVA in real-world settings. Methods: This US-based, multicenter, observational study used data from electronic medical records to evaluate real-world burden of illness before and after ELX/TEZ/IVA initiation in people with CF aged ≥12 years heterozygous for F508del and a minimal function mutation (F/MF) or an uncharacterized CFTR mutation. Endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI) and BMI-for-age z-score, glycated hemoglobin (HbA1c), and numbers of pulmonary exacerbations (PEx). Results: Overall, 206 people with CF were enrolled (mean [SD] age 22.5 [11.1] years; 192 [93.2%] with F/MF genotype). Mean follow-up was 15.6 (SD, 1.6) months. Improvements in ppFEV1 (7.3 [95% CI: 5.7, 8.8] percentage points) were observed from baseline through follow-up. Increases in BMI (1.40 [95% CI: 1.07, 1.77] kg/m2) and BMI-for-age z-score (0.14 [95% CI: 0.00, 0.28]) were also observed from baseline at 12 months. The estimated annualized rate of any PEx was 1.31 at baseline and 0.61 over follow-up (rate ratio 0.47 [95% CI: 0.39, 0.55]), with annualized rates of PEx requiring antibiotics and hospitalizations of 0.55 and 0.88 in the baseline period and 0.12 and 0.36 over follow-up (rate ratios 0.22 [95% CI: 0.15, 0.31] and 0.41 [95% CI: 0.32, 0.51]), respectively. Absolute change in HbA1c was -0.22 (95% CI: -0.38, -0.06) from baseline through follow-up. Conclusions: ELX/TEZ/IVA treatment was associated with improved lung function, increased BMI, reduced frequency of PEx, and improved (i.e., reduced) HbA1c. These results confirm the broad clinical benefits of ELX/TEZ/IVA seen in clinical trials and show the potential for ELX/TEZ/IVA to improve markers of glucose metabolism.

Psychometric performance of the CFQ-R-8D compared to the EQ-5D-3L and SF-6D in people with cystic fibrosis.

OBJECTIVE: This study aimed to compare the psychometric performance of the Cystic Fibrosis Questionnaire-Revised-8 Dimensions (CFQ-R-8D), a new, condition-specific, preference-based measure, with that of generic preference-based measures EQ-5D-3L and Short Form 6 dimensions (SF-6D). METHODS: Data from three trials of participants with CF aged ≥ 14 years who completed the CFQ-R and EQ-5D-3L or SF-6D were used. Analyses were undertaken to evaluate convergent validity based on correlations with CFQ-R domain scores. Known-group validity was assessed based on percent predicted forced expiratory volume in one second and pulmonary exacerbations. Responsiveness was based on correlation of change and sensitivity to change based on change in symptom severity. Effect sizes and standardized response means were estimated. RESULTS: CFQ-R-8D utilities and dimensions were strongly correlated with most of the overlapping CFQ-R domain scores (ρ > 0.5); EQ-5D-3L and SF-6D utilities and dimensions had moderate (ρ > 0.3) to strong correlations in dimensions capturing similar concepts. All measures showed evidence of known-group validity (P < 0.05). Change correlations were strong for CFQ-R-8D utilities and dimensions and CFQ-R, but they were moderate for SF-6D and mostly weak ((ρ > 0.1) for EQ-5D-3L. The SF-6D had the largest mean change over time and effect sizes, followed by CFQ-R-8D and then EQ-5D-3L. Neither CFQ-R-8D or SF-6D utility scores had ceiling effects (< 9% responses in full health) compared with those of EQ-5D-3L (61-62%). In participants classified as being in full health by EQ-5D-3L, CFQ-R-8D captured CF-specific health problems, particularly cough, abdominal pain, and breathing difficulty. CONCLUSIONS: The CFQ-R-8D reflected known-group differences and changes over time with stronger evidence of good psychometric performance than EQ-5D-3L and similar evidence as SF-6D. Additionally, the CFQ-R-8D captured more condition-specific symptoms than EQ-5D-3L or SF-6D, which are important determinants of health-related quality of life for people with CF.

Evaluation of Intratumoral Response Heterogeneity in Metastatic Colorectal Cancer and Its Impact on Patient Overall Survival: Findings from 10,551 Patients in the ARCAD Database.

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). PATIENTS AND METHODS: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. RESULTS: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. CONCLUSION: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.

Development of the Cystic Fibrosis Questionnaire-Revised-8 Dimensions: Estimating Utilities From the Cystic Fibrosis Questionnaire-Revised.

OBJECTIVES: Cystic fibrosis (CF) limits survival and negatively affects health-related quality of life (HRQOL). Cost-effectiveness analysis (CEA) may be used to make reimbursement decisions for new CF treatments; nevertheless, generic utility measures used in CEA, such as EQ-5D, are insensitive to meaningful changes in lung function and HRQOL in CF. Here we develop a new, CF disease-specific, preference-based utility measure based on the adolescent/adult version of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a widely used, CF-specific, patient-reported measure of HRQOL. METHODS: Blinded CFQ-R data from 4 clinical trials (NCT02347657, NCT02392234, NCT01807923, and NCT01807949) were used to identify discriminating items for a classification system using psychometric (eg, factor and Rasch) analyses. Thirty-two health states were selected for a time trade-off (TTO) exercise with a representative sample of the UK general population. TTO utilities were used to estimate a preference-based scoring algorithm by regression analysis (tobit models with robust standard errors clustered on participants with censoring at -1). RESULTS: A classification system with 8 dimensions (CFQ-R-8 dimensions; physical functioning, vitality, emotion, role functioning, breathing difficulty, cough, abdominal pain, and body image) was generated. TTO was completed by 400 participants (mean age, 47.3 years; 49.8% female). Among the regression models evaluated, the tobit heteroscedastic-ordered model was preferred, with a predicted utility range from 0.236 to 1, no logical inconsistencies, and a mean absolute error of 0.032. CONCLUSION: The CFQ-R-8 dimensions is the first disease-specific, preference-based scoring algorithm for CF, enabling estimation of disease-specific utilities for CEA based on the well-validated and widely used CFQ-R.

EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ≥ 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1 second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points [95% CI, -0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, -2.16 to -1.69) in ppFEV1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period.

Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.

BACKGROUND: Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation. METHODS: We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV1 of 40-90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV1, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972. FINDINGS: Between Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (-1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], p<0·0001), the mean percent predicted FEV1 increased by 11·2 percentage points (95% CI 9·8 to 12·6) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·0 percentage points (-0·4 to 2·4) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 10·2 percentage points [8·2 to 12·1], p<0·0001), and the mean sweat chloride concentration decreased by 46·2 mmol/L (95% CI 43·7 to 48·7) in the elexacaftor plus tezacaftor plus ivacaftor group and by 3·4 mmol/L (1·0 to 5·8) in the tezacaftor plus ivacaftor group (least squares mean treatment difference -42·8 mmol/L [-46·2 to -39·3], nominal p<0·0001). Most participants (70 [80%] in the elexacaftor plus tezacaftor plus ivacaftor group and 74 [84%] in the tezacaftor plus ivacaftor group) had adverse events that were mild or moderate in severity; serious adverse events occurred in five (6%) of 87 participants in the elexacaftor plus tezacaftor plus ivacaftor group and 14 (16%) of 88 participants in the tezacaftor plus ivacaftor group. One (1%) participant in the elexacaftor plus tezacaftor plus ivacaftor group discontinued treatment due to an adverse event of anxiety and depression. Two (2%) participants in the tezacaftor plus ivacaftor group discontinued treatment due to adverse events of psychotic disorder (n=1) and obsessive-compulsive disorder (n=1). INTERPRETATION: The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population. FUNDING: Vertex Pharmaceuticals.

The Contribution of Patient, Primary Care Physician, and Primary Care Clinic Factors to Good Bone Health Care.

BACKGROUND/OBJECTIVE: Patient, provider, and system factors can contribute to chronic care management and outcomes. Few studies have examined these multilevel associations with osteoporosis care and outcomes. We examined how key process and structural factors at the patient, primary care physician (PCP), and primary care clinic (PCC) levels were associated with guideline concordant osteoporosis pharmacotherapy, daily calcium intake, vitamin D supplementation, and weekly exercise sessions at 52 weeks following enrollment in a cluster randomized controlled trial. METHODS: We conducted a secondary analysis of observational data from 1 site of the trial. The study sample included 1996 men and women ≥ 50 years of age at the time of recruitment following completion of a dual-energy x-ray absorptiometry (DXA) scan and who had complete data at baseline and 52 weeks. Our primary independent variable was "relationship continuity": the DXA-ordering provider was the patient's PCP. Hierarchical linear and logistic regression accounted for patient, provider, and primary care clinic characteristics. RESULTS: In multivariable regression analyses, relationship continuity (ie, the PCP ordered the study DXA) was associated with higher average daily calcium intake and likelihood of vitamin D supplementation at 52 weeks. No PCP or primary care clinic factors were associated with osteoporosis care. CONCLUSIONS: The relationship continuity, in which the provider ordering a DXA is the patient's PCP and therefore also presents the results of a DXA, may help to promote patient behaviors associated with good bone health.

Assessing the ratio of means as a causal estimand in clinical endpoint bioequivalence studies in the presence of intercurrent events.

In clinical endpoint bioequivalence studies, the observed per-protocol (PP) population (compliers and completers in general) is usually used in the primary analysis for equivalence assessment. However, intercurrent events, ie, missingness and noncompliance, are not properly handled. The resulting estimand is not causal. Previously, we proposed the first causal framework to assess equivalence in the presence of missing data and noncompliance. We proposed a causal survivor average causal effect (SACE) estimand for the difference of means (DOM). In equivalence assessment, DOM is not as widely used as the ratio of means (ROM). However, no existing formula links the observed PP estimand to the SACE estimand for ROM as exists for DOM. Herein, we propose a similar causal framework for ROM using the principal stratification approach, one of the strategies recommended by the International Conference on Harmonisation (ICH) E9 R1 addendum. We quantify the bias of the observed ROM PP estimand for the SACE estimand, which provides a basis to identify three conditions under which the two estimands are equal. We propose a sensitivity analysis method to evaluate the robustness of the current PP estimator to estimate the SACE estimand. We extend Fieller's confidence interval for the SACE estimand using ROM, which can be applied to many settings. Simulation demonstrates that the PP estimator is biased in either directions and may inflate type 1 error and/or change power when the three identified conditions are violated. Our work can be applied to comparative clinical biosimilar studies.

Characteristics of older adults using patient web portals to view their DXA results.

BACKGROUND: Sharing test results with patients via patient web portals is a new trend in healthcare. No research has been done examining patient web portal use with bone density test results. The objective of our study was to identify patient characteristics associated with the use of patient web portals to view their bone density test results. METHODS: A secondary analysis of data from a pragmatic randomized controlled trial of 7749 participants ≥50 years old that had presented for a dual energy X-ray absorptiometry (DXA) bone density test. Patients were interviewed at enrollment and 12 weeks later. Multivariable logistic regression identified patient characteristics that differentiated those who used the web portal from those who did not. RESULTS: Our sample included 4669 patients at the two (University of Iowa [UI], and Kaiser Permanente of Georgia [KPGA]) clinical sites that had patient web portals. Of these patients, 3399 (72.8%) reported knowing their test results 12 weeks post-DXA, with 649 (13.9%) reporting that they viewed their DXA results using the web portal. Web portal users were more likely to be from UI than KPGA, and were younger, more educated, had higher health literacy, had osteopenia, and had the same sex as their referring physician (all p < 0.05). CONCLUSION: Only 19.1% of the 3399 patients who knew their DXA results used the available patient web portals to find out about them. Web portal users differed from non-users on several characteristics. This suggests that simply making patient web portals available for use may not be sufficient to appreciably enhance patient awareness of their test results. Based on these findings, a better understanding of the reasons why older, less educated, and less activated patients do not access their test results through patient web portals is needed.

Estimation of causal effects in clinical endpoint bioequivalence studies in the presence of intercurrent events: noncompliance and missing data.

In clinical endpoint bioequivalence (BE) studies, the primary analysis for assessing equivalence between a generic and an innovator product is based on the observed per-protocol (PP) population (usually completers and compliers). However, missing data and noncompliance are post-randomization intercurrent events and may introduce selection bias. Therefore, PP analysis is generally not causal. The FDA Missing Data Working Group recommended using "causal estimands of primary interest." In this paper, we propose a principal stratification causal framework and co-primary causal estimands to test equivalence, which was also recommended by the recently published ICH E9 (R1) addendum to address intercurrent events. We identify three conditions under which the current PP estimator is unbiased for one of the proposed co-primary causal estimands - the "Survivor Average Causal Effect" (SACE) estimand. Simulation shows that when these three conditions are not met, the PP estimator is biased and may inflate Type 1 error and/or change power. We also propose a tipping point sensitivity analysis to evaluate the robustness of the current PP estimator in testing equivalence when the sensitivity parameters deviate from the three identified conditions, but stay within a clinically meaningful range. Our work is the first causal equivalence assessment in equivalence studies with intercurrent events.

The prevalence of overtreatment of osteoporosis: results from the PAADRN trial.

Overtreatment of osteoporosis increases costs and puts patients at unnecessary risk of experiencing adverse drug events. In the Patient Activation After DXA Receipt Notification (PAADRN) trial, we found that 8% of individuals with no indication for therapy were recommended a new osteoporosis medication or continuation of an existing medication. PURPOSE: There is a robust body of literature addressing undertreatment in osteoporosis, but limited data addressing overtreatment. Understanding overtreatment is important to minimize harm and decrease costs. METHODS: One of the pre-specified post hoc analyses of the PAADRN trial, a randomized, controlled, pragmatic clinical trial, was to quantify and identify risk factors associated with osteoporosis overtreatment. PAADRN included patients ≥ 50 years of age presenting for bone density testing between February, 2012, and August, 2014, at three US healthcare systems. We assessed 20,397 patients for eligibility and randomized 7749. Intervention patients received a tailored letter containing their dual-energy X-ray absorptiometry (DXA) results and an educational osteoporosis brochure. Control patients received usual care. Using the National Osteoporosis Foundation treatment guidelines, we defined overtreatment as the receipt of osteoporosis pharmacotherapy 12 weeks after DXA when treatment was not indicated. We evaluated the relationship between the following baseline variables-sex, race/ethnicity, educational attainment, and differences across health systems-and overtreatment using a series of multivariable logistic regression models. RESULTS: Among 3602 patients with no apparent indication for osteoporosis treatment, 292 (8.1%; 95% CI, 7.22 to 9.00%) received a new prescription for osteoporosis pharmacotherapy or were instructed to continue an existing medication (presumed overtreatment). Presumed overtreatment was more common among participants with prior DXA history, those who reported a history of osteoporosis or low bone mass, and those referred for testing by family medicine providers. CONCLUSION: In our sample of older adults, overuse of osteoporosis pharmacotherapy was only 8.1%. Nevertheless, overtreatment exposes patients to possible risk with negligible chance of benefit and should be minimized. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01507662.

Diet and exercise changes following bone densitometry in the Patient Activation After DXA Result Notification (PAADRN) study.

Calcium and vitamin D intake and exercise are suboptimal among older adults. Following bone densitometry, a letter communicating individualized fracture risk accompanied by an educational brochure improved participants' lifestyle-but no more than existing communication strategies-over 52 weeks. Simple communication strategies are insufficient for achieving optimal levels of bone health behaviors. PURPOSE: The Patient Activation After DXA Result Notification (PAADRN) study was designed to evaluate whether a letter with individualized fracture risk and an educational brochure mailed to patients soon after their DXA might improve bone health behaviors (daily calcium intake, vitamin D supplementation, and weekly exercise sessions) compared to slower, less individualized communication characterizing usual care. METHODS: Participants ≥ 50 years were recruited, at three sites, following their DXA and randomized with 1:1 allocation to intervention and control (usual care only) groups. Data were collected at enrollment interview and by phone survey at 12 and 52 weeks thereafter. Intention-to-treat analyses were conducted on 7749 of the 20,397 eligible participants who enrolled. Changes in bone health behaviors were compared within and between study groups. Average treatment effects and heterogeneity of treatment effects were estimated with multivariable linear and logistic regression models. RESULTS: In unadjusted analyses, calcium intake, vitamin D supplementation, and weekly exercise sessions increased significantly over 52 weeks within both the intervention and control groups (all p < 0.001). In unadjusted analyses and multivariable models, increases in each behavior did not significantly differ between the intervention and control groups. Intervention group participants with a > 20% 10-year fracture risk at enrollment did, however, have a significantly greater increase in calcium intake compared to other study participants (p = 0.031). CONCLUSIONS: Bone health behaviors improved, on average, over 52 weeks among all participants following a DXA. Receipt of the PAADRN letter and educational brochure did not directly improve bone health behaviors compared to usual care. TRIAL REGISTRATION: The Patient Activation after DXA Result Notification (PAADRN) Study is registered at ClinicalTrials.Gov: NCT01507662, https://clinicaltrials.gov/ct2/show/NCT01507662.

Evaluation of a "Just-in-Time" Nurse Consultation on Bone Health: A Pilot Randomized Controlled Trial.

CONTEXT: Evidence is inconclusive whether a nurse consultation can improve osteoporosis-related patient outcomes. OBJECTIVE: To evaluate whether a nurse consultation immediately after dual-energy x-ray absorptiometry (DXA) produced better osteoporosis-related outcomes than a simple intervention to activate adults in good bone health practices or usual care. DESIGN: Pilot randomized controlled trial, conducted within the larger Patient Activation After DXA Result Notification (PAADRN) trial (NCT01507662). After DXA, consenting adults age 50 years or older were randomly assigned to 3 groups: nurse consultation, PAADRN intervention (mailed letter with individualized fracture risk and an educational brochure), or usual care (control). Nurse consultation included reviewing DXA results, counseling on bone health, and ordering needed follow-up tests or physician referrals. MAIN OUTCOME MEASURES: Change from baseline to 52 weeks in participant-reported osteoporosis-related pharmacotherapy, lifestyle, activation and self-efficacy, and osteoporosis care satisfaction. RESULTS: Nurse consultation participants (n = 104) reported 52-week improvements in strengthening and weight-bearing exercise (p = 0.09), calcium intake (p < 0.01), osteoporosis knowledge (p = 0.04), activation (p < 0.01), dietary self-efficacy (p = 0.06), and osteoporosis care satisfaction (p < 0.01). Compared with PAADRN intervention participants (n = 39), nurse consultation participants had improved dietary self-efficacy (p = 0.07) and osteoporosis care satisfaction (p = 0.05). No significant improvements in osteoporosis-related outcomes were achieved vs PAADRN controls (n = 70). CONCLUSION: "Just-in-time" nurse consultation yielded a few improvements over 52 weeks in osteoporosis-related outcomes; however, most changes were not different from those obtained through the lower-cost PAADRN intervention or usual care.

Patient-reported reasons for nonadherence to recommended osteoporosis pharmacotherapy.

OBJECTIVES: As many as one-half of patients recommended for osteoporosis pharmacotherapy do not take their medications. To identify intervention targets, we examined patient characteristics associated with nonadherence to recommended pharmacotherapy and their reasons for nonadherence. METHODS: Data come from the Patient Activation after DXA Result Notification (PAADRN) study, a randomized controlled trial of 7749 patients aged 50 years or older presenting for dual-energy X-ray absorptiometry (DXA) at 3 health centers in the United States. We focused on the 790 patients who reported receiving a recommendation for new pharmacotherapy at baseline. Using Pearson chi-squared tests for categorical variables, 2-sample t tests for continuous variables, and multivariable multinomial logistic regression, we compared those who reported starting the recommended medication (adherers) with temporary nonadherers and nonadherers on demographics, health habits, DXA impression, 10-year probability of fracture using the assessment tool, and osteoporosis knowledge, and we examined their stated reasons for nonadherence. RESULTS: Mean age was 66.8 years (SD = 8.9); 87.2% were women, and 84.2% were white. One-fourth of patients (24.8%) reported that they did not start their recommended pharmacotherapy. In the unadjusted analyses, the only factor significantly associated with nonadherence was osteoporosis knowledge, with those having better knowledge being less likely to take their medications (P < 0.05). The most common reasons for nonadherence were fear of adverse effects (53.3%), a dislike of taking medicine (25.3%), and the belief that the medication would not help their condition (16.7%). CONCLUSION: One in 4 patients recommended for osteoporosis pharmacotherapy declined treatment because they feared potential adverse effects, did not like taking medicine, or believed that the medication would not help their condition. Improved patient counseling on the potential adverse effects of osteoporosis treatment and the risk-benefit ratio for these medications may increase adherence.

Racial Differences and Disparities in Osteoporosis-related Bone Health: Results From the PAADRN Randomized Controlled Trial.

BACKGROUND: Determining whether observed differences in health care can be called disparities requires persistence of differences after adjustment for relevant patient, provider, and health system factors. We examined whether providing dual-energy x-ray absorptiometry (DXA) test results directly to patients might reduce or eliminate racial differences in osteoporosis-related health care. DESIGN, SUBJECTS, AND MEASURES: We analyzed data from 3484 white and 1041 black women who underwent DXA testing at 2 health systems participating in the Patient Activation after DXA Result Notification (PAADRN) pragmatic clinical trial (ClinicalTrials.gov NCT-01507662) between February 2012 and August 2014. We examined 7 outcomes related to bone health at 12 weeks and 52 weeks post-DXA: (1) whether the patient correctly identified their DXA baseline results; (2) whether the patient was on guideline-concordant osteoporosis pharmacotherapy; (3) osteoporosis-related satisfaction; (4) osteoporosis knowledge; (5 and 6) osteoporosis self-efficacy for exercise and for diet; and (7) patient activation. We examined whether unadjusted differences in outcomes between whites and blacks persisted after adjusting for patient, provider, and health system factors. RESULTS: Mean age was 66.5 years and 29% were black. At baseline black women had less education, poorer health status, and were less likely to report a history of osteoporosis (P<0.001 for all). In unadjusted analyses black women were less likely to correctly identify their actual DXA results, more likely to be on guideline-concordant therapy, and had similar patient activation. After adjustment for patient demographics, baseline health status and other factors, black women were still less likely to know their actual DXA result and less likely to be on guideline-concordant therapy, but black women had greater patient activation. CONCLUSIONS: Adjustment for patient and provider level factors can change how racial differences are viewed, unmasking new disparities, and providing explanations for others.

Activating Patients With a Tailored Bone Density Test Results Letter and Educational Brochure: the PAADRN Randomized Controlled Trial.

In cross-sectional studies, patient activation has been associated with better health behaviors, health outcomes, and health-care experiences. Moreover, tailored interventions have led to clinically meaningful improvements in patient activation, as well as health outcomes over time. We tested whether a tailored patient-activation letter communicating bone mineral density (BMD) test results plus an educational brochure improved patient activation scores and levels at 12 and 52 wk post-baseline as the mechanism leading to enhanced bone healthcare. In a randomized, controlled, double-blinded, multicenter pragmatic clinical trial, we randomized 7749 patients ≥50 yr old and presenting for BMD testing at 3 medical centers in the United States between February 2012 and August 2014. The outcome measures were patient activation scores and levels based on 6 items taken from the Patient Activation Measure (PAM) that were administered at the baseline, 12-wk, and 52-wk follow-up interviews. Mean age was 66.6 yr, 83.8% were women, and 75.3% were Non-Hispanic-Whites. Overall, PAM activation scores improved from 58.1 at baseline to 76.4 by 12 wk (p < 0.001) and to 77.2 (p = 0.002) by 52 wk post-baseline. These improvements, however, were not significantly different between the intervention and usual care groups (18.7 vs 18.1, p = 0.176, at 12 wk) in intention-to-treat analyses. PAM activation scores and levels substantially improved at 12 wk and 52 wk, but no differences were observed in these improvements between the intervention and usual care groups. These null findings may have occurred because the tailoring focused on the patient's BMD and fracture risk results, rather than on the patient's BMD and fracture risk results as well as the patient's baseline PAM activation scores or levels.

Improved Automated Detection of Diabetic Retinopathy on a Publicly Available Dataset Through Integration of Deep Learning.

PURPOSE: To compare performance of a deep-learning enhanced algorithm for automated detection of diabetic retinopathy (DR), to the previously published performance of that algorithm, the Iowa Detection Program (IDP)-without deep learning components-on the same publicly available set of fundus images and previously reported consensus reference standard set, by three US Board certified retinal specialists. METHODS: We used the previously reported consensus reference standard of referable DR (rDR), defined as International Clinical Classification of Diabetic Retinopathy moderate, severe nonproliferative (NPDR), proliferative DR, and/or macular edema (ME). Neither Messidor-2 images, nor the three retinal specialists setting the Messidor-2 reference standard were used for training IDx-DR version X2.1. Sensitivity, specificity, negative predictive value, area under the curve (AUC), and their confidence intervals (CIs) were calculated. RESULTS: Sensitivity was 96.8% (95% CI: 93.3%-98.8%), specificity was 87.0% (95% CI: 84.2%-89.4%), with 6/874 false negatives, resulting in a negative predictive value of 99.0% (95% CI: 97.8%-99.6%). No cases of severe NPDR, PDR, or ME were missed. The AUC was 0.980 (95% CI: 0.968-0.992). Sensitivity was not statistically different from published IDP sensitivity, which had a CI of 94.4% to 99.3%, but specificity was significantly better than the published IDP specificity CI of 55.7% to 63.0%. CONCLUSIONS: A deep-learning enhanced algorithm for the automated detection of DR, achieves significantly better performance than a previously reported, otherwise essentially identical, algorithm that does not employ deep learning. Deep learning enhanced algorithms have the potential to improve the efficiency of DR screening, and thereby to prevent visual loss and blindness from this devastating disease.

A pilot study among older adults of the concordance between their self-reports to a health survey and spousal proxy reports on their behalf.

BACKGROUND: Proxy respondents are frequently used in health surveys, and the proxy is most often the spouse. Longstanding concerns linger, however, about the validity of using spousal proxies, especially for older adults. The purpose of this pilot study was to evaluate the concordance between self-reports and spousal proxy reports to a standard health survey in a small convenience sample of older married couples. METHODS: We used the Seniors Together in Aging Research (STAR) volunteer registry at the University of Iowa to identify and consent a cross-sectional, convenience sample of 28 married husband and wife couples. Private, personal interviews with each member of the married couple using a detailed health survey based on the 2012 Health and Retirement Study (HRS) instrument were conducted using computer assisted personal interviewing software. Within couples, each wife completed the health survey first for herself and then for her husband, and each husband completed the health survey first for himself and then for his wife. The health survey topics included health ratings, health conditions, mobility, instrumental activities of daily living (IADLs), health services use, and preventative services. Percent of agreement and prevalence and bias adjusted kappa statistics (PABAKs) were used to evaluate concordance. RESULTS: PABAK coefficients indicated moderate to excellent concordance (PABAKs >0.60) for most of the IADL, health condition, hospitalization, surgery, preventative service, and mobility questions, but only slight to fair concordance (PABAKs = -0.21 to 0.60) for health ratings, and physician and dental visits. CONCLUSIONS: These results do not allay longstanding concerns about the validity of routinely using spousal proxies in health surveys to obtain health ratings or the number of physician and dental visits among older adults. Further research is needed in a nationally representative sample of older couples in which each wife completes the health survey first for herself and then for her husband, each husband completes the health survey first for himself and then for his wife, and both spouses' Medicare claims are linked to their health survey responses to determine not just the concordance between spousal reports, but the concordance of those survey responses to the medical record.

Effects of a DXA result letter on satisfaction, quality of life, and osteoporosis knowledge: a randomized controlled trial.

BACKGROUND: Undiagnosed, or diagnosed and untreated osteoporosis (OP) increases the likelihood that falls result in hip fractures, decreased quality of life (QOL), and significant medical expenditures among older adults. We tested whether a tailored dual energy x-ray absorptiometry (DXA) test result letter and an accompanying educational bone-health brochure affected patient satisfaction, QOL, or OP knowledge. METHODS: The Patient Activation after DXA Result Notification (PAADRN) study was a double-blinded, pragmatic, randomized trial which enrolled patients from 2012 to 2014. We randomized 7,749 patients presenting for DXA at three health care institutions in the United States who were ≥ 50 years old and able to understand English. Intervention patients received a tailored letter four weeks after DXA containing their results, 10-year fracture risk, and a bone-health educational brochure. Control patients received the results of their DXA per the usual practices of their providers and institutions. Satisfaction with bone health care, QOL, and OP knowledge were assessed at baseline and 12- and 52-weeks after DXA. Intention-to-treat analyses used multiple imputation for missing data and random effects regression models to adjust for clustering within providers and covariates. RESULTS: At 12-weeks 6,728 (86.8 %) and at 52-weeks 6,103 participants (78.8 %) completed their follow-up interviews. The intervention group was more satisfied with their bone health care compared to the usual care group at both their 12- and 52-week follow-ups (standardized effect size = 0.28 at 12-weeks and 0.17 at 52-weeks, p < 0.001). There were no differences between the intervention and usual care groups in QOL or OP knowledge at either time point. CONCLUSIONS: A tailored DXA result letter and bone-health educational brochure sent to patients improved patient satisfaction with bone-related health care. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01507662 First received: December 8, 2011.

Does the Relationship of the Proxy to the Target Person Affect the Concordance between Survey Reports and Medicare Claims Measures of Health Services Use?

OBJECTIVES: To compare concordance of survey reports of health service use versus claims data between self respondents and spousal and nonspousal relative proxies. DATA SOURCES: 1995-2010 data from the Survey on Assets and Health Dynamics among the Oldest Old and 1993-2010 Medicare claims for 3,229 individuals (13,488 person-years). STUDY DESIGN: Regression models with individual fixed effects were estimated for discordance of any hospitalizations and outpatient surgery and for the numbers of under- and over-reported physician visits. PRINCIPAL FINDINGS: Spousal proxies were similar to self respondents on discordance. Nonspousal proxies, particularly daughters/daughters-in-law and sons/sons-in-law, had less discordance, mainly due to reduced under-reporting. CONCLUSIONS: Survey reports of health services use from nonspousal relatives are more consistent with Medicare claims than spousal proxies and self respondents.