Publications by authors named "Lauren Nelson"

63 Publications

Implementation of the QUBE Force Field in SOMD for High-Throughput Alchemical Free-Energy Calculations.

J Chem Inf Model 2021 Apr 22. Epub 2021 Apr 22.

School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom.

The quantum mechanical bespoke (QUBE) force-field approach has been developed to facilitate the automated derivation of potential energy function parameters for modeling protein-ligand binding. To date, the approach has been validated in the context of Monte Carlo simulations of protein-ligand complexes. We describe here the implementation of the QUBE force field in the alchemical free-energy calculation molecular dynamics simulation package SOMD. The implementation is validated by demonstrating the reproducibility of absolute hydration free energies computed with the QUBE force field across the SOMD and GROMACS software packages. We further demonstrate, by way of a case study involving two series of non-nucleoside inhibitors of HIV-1 reverse transcriptase, that the availability of QUBE in a modern simulation package that makes efficient use of graphics processing unit acceleration will facilitate high-throughput alchemical free-energy calculations.
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http://dx.doi.org/10.1021/acs.jcim.1c00328DOI Listing
April 2021

Photoperiod Manipulation Reveals a Light-Driven Component to Daily Patterns of Ventilation in Male C57Bl/6J Mice.

J Biol Rhythms 2021 Mar 8:748730421992581. Epub 2021 Mar 8.

Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin.

Obstructive sleep apnea is a common sleep disorder that increases risk for cardiovascular disease and mortality. The severity of sleep-disordered breathing in obstructive sleep apnea patients fluctuates with the seasons, opening the possibility that seasonal changes in light duration, or photoperiod, can influence mechanisms of breathing. Photoperiod can have profound effects on internal timekeeping and can reshape metabolic rhythms in mammals. While the daily rhythm in ventilation is largely shaped by the metabolic rate, less is known about whether ventilatory rhythms are altered in accordance with metabolism under different photoperiods. Here, we investigate the relationship between ventilation and metabolism under different photoperiods using whole-body plethysmography and indirect calorimetry. We find that the daily timing of ventilation is chiefly synchronized to dark onset and that light cues are important for maintaining daily ventilatory rhythms. Moreover, changes in ventilatory patterns are not paralleled by changes in oxygen consumption, energy expenditure, or respiratory exchange rate under different photoperiods. We conclude that ventilatory patterns are not only shaped by the metabolic rate and circadian timing but are also influenced by other light-driven factors. Collectively, these findings have clinical implications for the seasonal variations in sleep-disordered breathing found in individuals with obstructive sleep apnea.
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http://dx.doi.org/10.1177/0748730421992581DOI Listing
March 2021

Role of t-tubule remodeling on mechanisms of abnormal calcium release during heart failure development in canine ventricle.

Am J Physiol Heart Circ Physiol 2021 04 26;320(4):H1658-H1669. Epub 2021 Feb 26.

Feinberg Cardiovascular and Renal Research Institute and Department of Medicine (Cardiology), Northwestern University Feinberg School of Medicine, Chicago, Illinois.

The goal of this work was to investigate the role of t-tubule (TT) remodeling in abnormal Ca cycling in ventricular myocytes of failing dog hearts. Heart failure (HF) was induced using rapid right ventricular pacing. Extensive changes in echocardiographic parameters, including left and right ventricular dilation and systolic dysfunction, diastolic dysfunction, elevated left ventricular filling pressures, and abnormal cardiac mechanics, indicated that severe HF developed. TT loss was extensive when measured as the density of total cell volume, derived from three-dimensional confocal image analysis, and significantly increased the distances in the cell interior to closest cell membrane. Changes in Ca transients indicated increases in heterogeneity of Ca release along the cell length. When critical properties of Ca release variability were plotted as a function of TT organization, there was a complex, nonlinear relationship between impaired calcium release and decreasing TT organization below a certain threshold of TT organization leading to increased sensitivity in Ca release below a TT density threshold of 1.5%. The loss of TTs was also associated with a greater incidence of triggered Ca waves during rapid pacing. Finally, virtually all of these observations were replicated by acute detubulation by formamide treatment, indicating an important role of TT remodeling in impaired Ca cycling. We conclude that TT remodeling itself is a major contributor to abnormal Ca cycling in HF, reducing myocardial performance. The loss of TTs is also responsible for a greater incidence of triggered Ca waves that may play a role in ventricular arrhythmias arising in HF. Three-dimensional analysis of t-tubule density showed t-tubule disruption throughout the whole myocyte in failing dog ventricle. A double-linear relationship between Ca release and t-tubule density displays a steeper slope at t-tubule densities below a threshold value (∼1.5%) above which there is little effect on Ca release (T-tubule reserve). T-tubule loss increases incidence of triggered Ca waves. Chemically induced t-tubule disruption suggests that t-tubule loss alone is a critical component of abnormal Ca cycling in heart failure.
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http://dx.doi.org/10.1152/ajpheart.00946.2020DOI Listing
April 2021

The Rapid Mood Screener (RMS): a novel and pragmatic screener for bipolar I disorder.

Curr Med Res Opin 2021 Jan 6;37(1):135-144. Epub 2021 Jan 6.

School of Medicine, Texas Tech University - Permian Basin, Midland, TX, USA.

Objective: Depressive episodes and symptoms of bipolar I disorder are commonly misdiagnosed as major depressive disorder (MDD) in primary care. The novel and pragmatic Rapid Mood Screener (RMS) was developed to screen for manic symptoms and bipolar I disorder features (e.g. age of depression onset) to address this unmet clinical need.

Methods: A targeted literature search was conducted to select concepts thought to differentiate bipolar I from MDD and screener tool items were drafted. Items were tested and refined in cognitive debriefing interviews with individuals with self-reported bipolar I or MDD ( = 12). An observational study was conducted to evaluate predictive validity. Participants with clinical interview-confirmed bipolar I or MDD diagnoses ( = 139) completed a draft 10-item screening tool and other questionnaires. Data were analyzed to identify the smallest possible subset of items with optimized sensitivity and specificity.

Results: Adults with confirmed bipolar I ( = 67) or MDD ( = 72) participated in the observational study. Ten draft screening tool items were reduced to 6 final RMS items based on the item-level analysis. When 4 or more items of the RMS were endorsed ("yes"), sensitivity was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. These properties were an improvement over the Mood Disorder Questionnaire in the same analysis sample while using 60% fewer items.

Conclusion: The pragmatic 6-item RMS differentiates bipolar I disorder from MDD in patients with depressive symptoms, providing real-world guidance to primary care practitioners on whether a more comprehensive assessment for bipolar I disorder is warranted.
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http://dx.doi.org/10.1080/03007995.2020.1860358DOI Listing
January 2021

Psychometric evaluation of the DAILY EATS questionnaire in individuals living with obesity.

J Patient Rep Outcomes 2020 Nov 23;4(1):99. Epub 2020 Nov 23.

RTI Health Solutions, 3040 East Cornwallis Road, Post Office Box 12194, Research Triangle Park, NC, 27709-2194, USA.

Background: Physiological and behavioral factors including hunger, satiety, food intake, and cravings are health determinants contributing to obesity. Patient-reported outcome (PRO) measures focused on eating-related factors provide insight into the relationships between food choice and quantity, weight change, and weight-loss treatment for individuals living with obesity. The DAILY EATS is a novel 5-item, patient-reported measure evaluating key eating-related factors (Worst and Average Hunger, Appetite, Cravings, and Satiety).

Methods: Psychometric analyses, consistent with regulatory standards, were conducted to evaluate the DAILY EATS using data from two randomized trials that included individuals with severe obesity without diabetes (NCT03486392) and with severe obesity and type 2 diabetes (NCT03586830). Additional measures included Patient Global Impression of Status (PGIS) and Patient Global Impression of Change items, Impact of Weight on Quality of Life-Lite, Ease of Weight Management, and Patient-Reported Outcomes Measurement Information System Physical Function Short Form 8b and 10a. The reliability, validity, and responsiveness of the DAILY EATS were assessed, and a scoring algorithm and thresholds to interpret meaningful score changes were developed.

Results: Item-level analyses of the DAILY EATS supported computation of an Eating Drivers Index (EDI), comprising the related items Worst Hunger, Appetite, and Cravings. Internal consistency (Cronbach's coefficient alphas ≥0.80) and test-retest reliability (coefficients > 0.7) of the EDI were robust. Construct validity correlation patterns with other PRO measures were as hypothesized, with moderate to strong significant correlations between the EDI and PGIS-Hunger (0.30 ≤ r ≤ 0.68), PGIS-Cravings (0.33 ≤ r ≤ 0.77) and PGIS-Appetite (0.52 ≤ r ≤ 0.77). Anchor- and distribution-based analyses support reductions ranging from 1.6 to 2.1 as responder thresholds for the EDI, representing meaningful within-person improvement.

Conclusions: The DAILY EATS individual items and the composite EDI are reliable, sensitive, and valid in evaluating the concepts of hunger, appetite, and cravings for use in individuals with severe obesity with or without type 2 diabetes.
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http://dx.doi.org/10.1186/s41687-020-00259-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683653PMC
November 2020

Improving communication with patients in post-traumatic amnesia: development and impact of a clinical protocol.

Brain Inj 2020 09 23;34(11):1518-1524. Epub 2020 Aug 23.

School of Rehabilitation Science, McMaster University , Ontario, California, USA.

Objective: To assess the impact of staff training focused on improved treatment and communication with patients in post-traumatic amnesia (PTA) or other disorders of explicit (declarative) memory. A major aim was to minimize questions demanding recall from explicit memory, e.g., orientation quizzing, and personal/medical history questions, which may produce unreliable information and exacerbate patient frustration and anxiety.

Methods: Mixed-methods design. Inpatients with impairments of explicit memory were observed before (n = 4) and after (n = 4) training, with staff interactions recorded verbatim. Records were coded for types of questions and patient responses. Clinicians who worked before and after training were surveyed regarding perceived changes in practice, team functioning, and patient behavior.

Results: Explicit memory questions decreased significantly, as did irrelevant or "don't know" responses from patients, with large nonparametric effect sizes noted. The frequency of questions not relying on explicit memory remained stable. Most clinicians reported positive effects on their own and others' practice with memory impaired patients, and one-quarter noted less patient frustration or agitation.

Conclusions: Although questioning patients is a natural part of medical care, targeted staff training can result in positive changes in communication practice and should be considered for facilities treating patients in PTA.
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http://dx.doi.org/10.1080/02699052.2020.1809710DOI Listing
September 2020

Evaluating patient-perceived control of atopic dermatitis: design, validation, and scoring of the Atopic Dermatitis Control Tool (ADCT).

Curr Med Res Opin 2020 03 12;36(3):367-376. Epub 2019 Dec 12.

Health Economics Value Assessment, Sanofi, Chilly Mazarin, France.

The Atopic Dermatitis Control Tool (ADCT) was designed to evaluate patient-perceived AD control and facilitate patient-physician discussion on long-term disease control. The study was performed in adult patients with AD. Development of the ADCT followed US Food and Drug Administration (FDA) guidelines on patient-reported outcome measures (PROMs). Qualitative research, including targeted literature review, interviews with clinical experts, and combined concept elicitation/cognitive debriefing with patients with AD, was conducted to provide a list of comprehensive concepts capturing AD control per physician and patient perspectives. Quantitative methods assessed psychometric properties of the instrument and defined the threshold for AD control. The resulting pilot six-item ADCT, reflecting key concepts related to AD control, had 7-day recall and assessed symptoms and impacts on patients' everyday lives by severity and/or frequency. The ADCT showed good content validity (well understood by adult patients with AD), and quick completion time (<2 min). Psychometric analysis indicated no floor/ceiling effects for response distributions, particularly strong ( ≥ 0.80) inter-item correlations for the six ADCT items, robust construct validity ( > 0.50), and item-level discriminating ability ( < .03); this supported the derivation of a total score based on responses to all items. ADCT total score showed evidence of strong internal consistency reliability (Cronbach's alpha >0.80). A score ≥7 points was identified as an optimum threshold to identify patients whose AD is "not in control." No single validated instrument has been available to holistically evaluate patient-perceived AD control. The newly developed ADCT displays good-to-excellent content validity, construct validity, internal consistency, reliability, and discriminating ability.
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http://dx.doi.org/10.1080/03007995.2019.1699516DOI Listing
March 2020

Validation of the Atopic Dermatitis Control Tool (ADCT©) using a longitudinal survey of biologic-treated patients with atopic dermatitis.

BMC Dermatol 2019 11 6;19(1):15. Epub 2019 Nov 6.

Eastern Virginia Medical School, Norfolk, VA, USA.

Background: The Atopic Dermatitis Control Tool (ADCT©) is a brief patient self-administered instrument designed and validated to assess atopic dermatitis (AD) control; six AD symptoms and impacts are evaluated over the past week, including overall severity of symptoms, days with intense episodes of itching, intensity of bother, problem with sleep, impact on daily activities, and impact on mood or emotions. This study assessed the reliability, validity, and responsiveness of the ADCT in a longitudinal context, and provided thresholds to identify meaningful within-person change.

Methods: Data were from a prospective, longitudinal patient survey study of real-world effectiveness of dupilumab in patients with AD. Eligible patients completed a baseline survey before starting dupilumab and were followed at Months 1, 2, 3, and 6 post-initiation as they became eligible.

Results: Psychometric analyses confirmed internal consistency; Cronbach's α coefficients were consistently above the threshold of 0.70 across each follow-up; item-to-total correlations were above the threshold of r ≥ 0.50. High correlations between the ADCT and the Dermatology Life Quality Index (DLQI) and skin pain supported construct validity, while known-group validity was shown on Patient Global Assessment of Disease (PGAD) overall well-being subgroups with worse AD-related overall well-being having higher mean ADCT total scores at all time points. The ability of the ADCT to detect change was confirmed; the threshold for meaningful within-person change was estimated to be 5 points. Finally, test-retest reliability was confirmed in subgroups of patients with stable PGAD responses.

Conclusions: Our findings confirm that the ADCT is a valid and reliable tool for assessing AD control.
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http://dx.doi.org/10.1186/s12895-019-0095-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833284PMC
November 2019

Responder Threshold for Patient-Oriented Eczema Measure (POEM) and Children's Dermatology Life Quality Index (CDLQI) in Adolescents with Atopic Dermatitis.

Dermatol Ther (Heidelb) 2019 Dec 22;9(4):799-805. Epub 2019 Oct 22.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

Introduction: The Patient-Oriented Eczema Measure (POEM) assesses patient-reported frequency of atopic dermatitis (AD) symptoms, while the Children's Dermatology Life Quality Index (CDLQI) measures the impact of skin disease on health-related quality of life (HRQoL) in children. There is currently no threshold for clinically meaningful within-person change in POEM or CDLQI scores in adolescents. Here we empirically derive within-person thresholds of meaningful within-person change in POEM and CDLQI scores in adolescents with moderate-to-severe AD.

Methods: Data were used from a phase 3, randomized, double-blind, placebo-controlled trial of dupilumab in adolescents (aged ≥ 12 to < 18 years) with moderate-to-severe AD. Anchor-based methods were employed using the mean change in POEM and CDLQI scores from baseline to week 16 linked with a 1-point improvement in Patient Global Assessment of Disease (PGAD), a score of "a little better" on the Patient Global Assessment of Treatment effect (PGAT), a 50-74% improvement from baseline in the Eczema Area and Severity Index (EASI-50-74), and a 1-point improvement in Investigator's Global Assessment (IGA) score.

Results: A mean change of - 7.8 and - 5.6 in the POEM score was associated with PGAD and PGAT anchors, respectively. EASI-50-74 was associated with a mean change in POEM score of - 8.2, while the IGA anchor was associated with a mean change of - 7.9 in POEM score. The mean changes in CDLQI score associated with PGAD and PGAT anchors were - 6.4 and - 6.6, respectively, while CDLQI mean scores changed by - 8.3 and - 8.0 for the EASI and IGA anchors, respectively.

Conclusion: In adolescents (aged ≥ 12 to < 18 years) with moderate-to-severe AD, a within-person change of 6-8 points in POEM and CDLQI scores, independently, can be considered a reasonable responder threshold for clinically meaningful change in each of the two scales, respectively.

Trial Registration: ClinicalTrials.gov Identifier: NCT03054428.

Funding: Sanofi and Regeneron Pharmaceuticals, Inc.
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http://dx.doi.org/10.1007/s13555-019-00333-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828922PMC
December 2019

The future of force fields in computer-aided drug design.

Future Med Chem 2019 09 23;11(18):2359-2363. Epub 2019 Sep 23.

School of Natural & Environmental Sciences, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.

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http://dx.doi.org/10.4155/fmc-2019-0196DOI Listing
September 2019

Development, psychometric evaluation, and initial feasibility assessment of a symptom tracker for use by patients with heart failure (HFaST).

J Patient Rep Outcomes 2019 May 2;3(1):26. Epub 2019 May 2.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Background: This study aimed to develop and provide a psychometric and feasibility pilot evaluation of the Heart Failure (HF) Symptom Tracker (HFaST), a new patient-reported tool designed to facilitate communication between patients and health care providers (HCPs) in routine clinical care. The HFaST enables patients to identify worsening HF symptoms, with a long-term goal of preventing hospitalizations or emergency room visits.

Methods: The HFaST was developed drawing on evidence from the literature, qualitatively with cognitive interviews (12 patient/caregiver and 8 HCPs), and evaluated quantitatively (psychometric, feasibility assessment). The HFaST was administered for 7 consecutive days to 100 individuals diagnosed with HF during a multisite, non-interventional US pilot study. Health care providers then completed a survey assessing the feasibility and importance of the HFaST in clinical practice. Qualitative development included a literature review and cognitive interviews with patients, caregivers, and HCPs. The psychometric properties of the HFaST were evaluated using classical test theory methods. Descriptive statistics provided insight into HCPs' perceptions of the feasibility of using the HFaST in clinical practice.

Results: A preliminary set of 40 items was developed for the symptom tracker and iteratively reduced to 10 items based on the qualitative phase. Test-retest reliability (weighted kappa 0.71-0.97), discriminating validity, and construct validity of the HFaST were acceptable. HCPs rated the HFaST as a good (70%) or excellent (30%) means of tracking HF symptoms. Six HFaST items were ultimately retained, covering concepts of fatigue, shortness of breath (3 items), swelling, and rapid weight gain.

Conclusions: The 6-item HFaST is an easy-to-use tool designed to raise patients' awareness of HF symptoms and facilitate communication with HCPs. Future research should evaluate HFaST implementation in clinical practice and effectiveness as an intervention to potentially prevent hospitalizations and emergency room visits.
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http://dx.doi.org/10.1186/s41687-019-0113-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497706PMC
May 2019

Development and psychometric evaluation of the Diabetic Gastroparesis Symptom Severity Diary.

Clin Exp Gastroenterol 2019 22;12:93-103. Epub 2019 Feb 22.

Patient-Centered Outcomes Research, Global Evidence and Value Development, Allergan plc, Madison, NJ, USA,

Background: Diabetic gastroparesis (DG) is defined as delayed gastric emptying with associated gastrointestinal symptoms, without mechanical obstruction. Patient-reported symptoms are critical for diagnosis and evaluation of treatment benefit in DG. The Diabetic Gastroparesis Symptom Severity Diary (DGSSD), a new patient-reported outcome measure, was developed for use in clinical trials to support product approval and labeling claims for DG treatments.

Materials And Methods: Initial DGSSD development was based on a review of the existing instruments and qualitative research (focus groups and cognitive debriefing interviews) in 41 patients with DG. Psychometric evaluations (individual items and composite scores) were conducted using data from Phase IIa and IIb relamorelin clinical trials.

Results: Qualitative research in patients with DG resulted in a six-item DGSSD, included in the Phase IIa trial, addressing symptom severity for nausea, vomiting, abdominal pain, early satiety, and bloating, as well as vomiting frequency. An item addressing severity of postprandial fullness (PPF) was subsequently added based on regulatory advice and included in the Phase IIb trial. Measurement properties were generally strong for weekly averages of daily item and composite scores. Item-level intraclass correlation coefficients ranged from 0.79 to 0.97 and correlations with other measures matched hypothesized patterns; the discriminating ability and responsiveness of the DGSSD were also supported. Multiple methods supported the computation of a composite score based on items addressing nausea, abdominal pain, bloating, and PPF severity.

Conclusion: Qualitative and quantitative evidence support use of the DGSSD as a reliable and valid measure from which to derive endpoints to evaluate treatment benefit in future DG interventional trials.
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http://dx.doi.org/10.2147/CEG.S184016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390855PMC
February 2019

Psychometric evaluation of the hypoparathyroidism symptom diary.

Patient Relat Outcome Meas 2019 29;10:25-36. Epub 2019 Jan 29.

RTI Health Solutions, Ann Arbor, MI, USA.

Purpose: To conduct an initial psychometric evaluation of the reliability and validity of the Hypoparathyroidism Symptom Diary (HPT-SD).

Patients And Methods: Data were collected during a cross-sectional, observational study. Participants with self-reported hypoparathyroidism (HPT) completed the HPT-SD, the Functional Assessment in Cancer Therapy-Cognitive Function (FACT-Cog), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and the Hospital Anxiety and Depression Scale (HADS) measures. Item- and scale-level internal consistency reliability, known-groups validity, and construct validity were evaluated. Subscales were identified and preliminary scoring algorithms were developed.

Results: The study included 52 participants (mean age, 51 years). Overall, the measurement properties of the HPT-SD were very good. Item-level response frequency distributions showed evidence of possible floor effects for four muscle-related symptom items. Inter-item correlations revealed a pattern of relationships among symptom items (=0.3-0.8) and among impact items (=0.5-0.7) and provided evidence for two HPT-SD subscales: Symptoms and Impacts. Construct validity correlations supported a priori convergent validity hypotheses (|r|≥0.4) between HPT-SD subscales and the FACT-Cog, FACIT-Fatigue, and HADS. Mean HPT-SD Symptom and Impact scores were in the expected direction and significantly different between subgroups of patients with high and low HPT disease severity.

Conclusion: Results indicate that the HPT-SD is an appropriate measure of HPT-related symptoms and impacts. Floor effects may be attributed to the observational study design: participants manage symptoms with calcium and active vitamin D supplements prior to an escalation in severity. Future studies should assess the HPT-SD measurement properties using longitudinal study designs.
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http://dx.doi.org/10.2147/PROM.S179310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357884PMC
January 2019

Assessing test-retest reliability of patient-reported outcome measures using intraclass correlation coefficients: recommendations for selecting and documenting the analytical formula.

Qual Life Res 2019 Apr 13;28(4):1029-1033. Epub 2018 Dec 13.

Critical Path Institute, 1730 E River Road, Tucson, AZ, 85718, USA.

Purpose: The US Food and Drug Administration (FDA) 2009 guidance for industry on patient-reported outcome (PRO) measures describes how the Agency evaluates the psychometric properties of measures intended to support medical product labeling claims. An important psychometric property is test-retest reliability. The guidance lists intraclass correlation coefficients (ICCs) and the assessment time period as key considerations for test-retest reliability evaluations. However, the guidance does not provide recommendations regarding ICC computation, nor is there consensus within the measurement literature regarding the most appropriate ICC formula for test-retest reliability assessment. This absence of consensus emerged as an issue within Critical Path Institute's PRO Consortium. The purpose of this project was to generate thoughtful and informed recommendations regarding the most appropriate ICC formula for assessing a PRO measure's test-retest reliability.

Methods: Literature was reviewed and a preferred ICC formula was proposed. Feedback on the chosen formula was solicited from psychometricians, biostatisticians, regulators, and other scientists who have collaborated on PRO Consortium initiatives.

Results And Conclusions: Feedback was carefully considered and, after further deliberation, the proposed ICC formula was confirmed. In conclusion, to assess test-retest reliability for PRO measures, the two-way mixed-effect analysis of variance model with interaction for the absolute agreement between single scores is recommended.
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http://dx.doi.org/10.1007/s11136-018-2076-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439259PMC
April 2019

Long-term health-related quality-of-life and symptom response profiles with arformoterol in COPD: results from a 52-week trial.

Int J Chron Obstruct Pulmon Dis 2018 5;13:499-508. Epub 2018 Feb 5.

Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA.

Background: Symptom severity is the largest factor in determining subjective health in COPD. Symptoms (eg, chronic cough, dyspnea) are associated with decreased health-related quality of life (HRQoL). We evaluated the impact of arformoterol on HRQoL in COPD patients, measured by St George's Respiratory Questionnaire (SGRQ). Post hoc growth mixture model (GMM) analysis examined symptom response profiles.

Methods: We examined data from a randomized, double-blind, parallel-group, 12-month safety trial of twice-daily nebulized arformoterol 15 µg (n=420) versus placebo (n=421). COPD severity was assessed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) status. GMM analysis identified previously unknown patient subgroups and examined the heterogeneity in response to SGRQ Symptoms scores.

Results: SGRQ Total score improved by 4.24 points with arformoterol and 2.02 points with placebo (=0.006). Significantly greater improvements occurred for arformoterol versus placebo in SGRQ Symptoms (6.34 vs 4.25, =0.031) and Impacts (3.91 vs 0.97, =0.001) scores, but not in Activity score (3.57 vs 1.75, =0.057). GMM identified responders and nonresponders based on the SGRQ Symptoms score. End-of-study mean difference in SGRQ Symptoms scores between these latent classes was 20.7 points (<0.001; 95% confidence interval: 17.6-23.9). Compared with nonresponders, responders were more likely current smokers (55.52% vs 44.02%, =0.0021) and had more severe COPD (forced expiratory volume in 1 second [FEV]: 1.16 vs 1.23 L, =0.0419), more exacerbations (0.96 vs 0.69, =0.0018), and worse mean SGRQ Total (59.81 vs 40.57, <0.0001), Clinical COPD Questionnaire (3.29 vs 2.05, <0.0001), and Modified Medical Research Council Dyspnea Scale (3.13 vs 2.75, <0.0001) scores. Arformoterol-receiving responders exhibited significantly greater improvements in FEV (0.09 vs 0.008, =0.03) and fewer hospitalizations (0.13 vs 0.24, =0.02) than those receiving placebo.

Conclusion: In this study, arformoterol treatment significantly improved HRQoL reflected by SGRQ. For the analysis performed on these data, arformoterol may be particularly effective in improving lung function and reducing hospitalizations among patients who are unable to quit smoking or present with more severe symptoms.
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http://dx.doi.org/10.2147/COPD.S141729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804733PMC
September 2018

Contraceptive Method Use and Chlamydia Positivity Among California Family Planning Clients: The Case for New Multipurpose Prevention Technologies.

J Womens Health (Larchmt) 2018 06 29;27(6):768-774. Epub 2018 Jan 29.

2 Sexually Transmitted Diseases (STD) Control Branch, Division of Communicable Disease Control (DCDC), Center for Infectious Diseases (CID) , California Department of Public Health (CDPH), Richmond, California.

Background: Adolescent girls and young women experience high rates of sexually transmitted infection (STI) with currently available contraceptive methods, yet few studies examine the burden of chlamydial infection by contraceptive method used.

Materials And Methods: In this cross-sectional analysis, we linked July 2012-June 2013 claims from a publicly-funded family planning program in California to chlamydia laboratory test results. Female clients were classified by the most effective contraceptive method reported by providers during the year: tier 1 (high-efficacy permanent or long-acting reversible methods), tier 2 (shorter-acting hormonal methods), or tier 3 (barrier methods, emergency contraception, or natural family planning). In addition, we identified clients who received condoms from providers. We used log-binomial models to estimate adjusted prevalence ratios comparing chlamydia positivity by contraceptive method(s).

Results: Of 74,636 female clients of ages 15-29 years with chlamydia test results, 5.1% had at least one positive test during the year. Chlamydia positivity was highest among tier 2 users (5.3%) compared with 4.5% and 4.9% among tiers 1 and 3 users, respectively (p < 0.001). Positivity was higher among clients who received condoms from providers than those who did not (6.3% vs. 4.3%, p < 0.001). In adjusted analyses, there were no significant differences in positivity by contraceptive tier. However, clients who received condoms had 1.32 (95% confidence interval: 1.24-1.40) times the positivity of those who did not.

Conclusions: We found high chlamydia positivity among young female family planning clients regardless of contraceptive method. The development and provision of additional Multipurpose Prevention Technologies that confer protection against both pregnancy and STIs may help to address unmet need for STI prevention.
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http://dx.doi.org/10.1089/jwh.2017.6558DOI Listing
June 2018

Quantifying the importance of inhaler attributes corresponding to items in the patient satisfaction and preference questionnaire in patients using Combivent Respimat.

Health Qual Life Outcomes 2017 Oct 16;15(1):201. Epub 2017 Oct 16.

RTI Health Solutions, 3040 Cornwallis Road, Post Office Box 12194, Research Triangle Park, Durham, NC, 27709-2194, UK.

Background: Physicians consider ease of use, satisfaction, and preferences when prescribing an inhaler device. These factors may impact appropriate usage and compliance.

Methods: The objectives were to quantify the relative importance of inhaler attributes in patients currently using Combivent Respimat by eliciting preferences for performance and convenience attributes assessed by items in the Patient Satisfaction and Preference Questionnaire (PASAPQ). Using a pharmacy database, 19,964 adults in the United States who filled ≥2 Combivent Respimat prescriptions were identified. Of those, 8150 patients were randomly selected to receive invitation letters. The online cross-sectional survey included the PASAPQ and best-worst scaling (BWS) questions. The PASAPQ measures satisfaction with medication attributes across two domains: performance and convenience. BWS questions asked participants to select the most and least important device attributes. A descriptive statistics analysis of the PASAPQ and a random-parameters logit model of BWS responses were conducted.

Results: The survey was completed by 503 participants. Most were female (57.3%), white (88.5%), and 51-70 years old (67.6%). Approximately 47% reported a chronic obstructive pulmonary disease diagnosis, 21.9% asthma, 8.2% other lung disease, and 23.1% more than one lung disease. PASAPQ scores indicated that the majority were satisfied or very satisfied; up to 20% reported being dissatisfied with Combivent Respimat. The three most important inhaler attributes were Feeling that your medicine gets into your lungs, Inhaler works reliably, and Inhaler makes inhaling your medicine easy. The most important attributes corresponded to six of seven items in the PASAPQ performance domain.

Conclusions: Most participants reported satisfaction with Combivent Respimat. Performance attributes were more important than convenience attributes.
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http://dx.doi.org/10.1186/s12955-017-0780-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644105PMC
October 2017

Use and Value of the 7-Item Binge Eating Disorder Screener in Clinical Practice.

Prim Care Companion CNS Disord 2017 Jun 29;19(3). Epub 2017 Jun 29.

RTI Health Solutions, Research Triangle Park, North Carolina, USA.

Objective: To evaluate physician knowledge of and attitudes about binge-eating disorder (BED) and the value and ease-of-use of the 7-item Binge Eating Disorder Screener (BEDS-7) in clinical practice.

Methods: Two internet surveys (wave 1: April 15-May 6, 2015; wave 2: August 19-25, 2015) were administered to primary care physicians serving adults (PCPs-adults) and psychiatrists. Wave 1 invitees were US-based physicians spending ≥ 50% of their time in direct patient care and reporting "no" to "some to average" experience with eating-disorder patients. Respondents completing wave 1 qualified for wave 2.

Results: Among the 1,047 physicians who responded, 313 did not meet at least 1 of the screening criteria, including 3.15% of respondents who spent < 50% of their time in direct patient care. Overall, 122 PCPs-adults and 123 psychiatrists completed both waves. Physician groups spent similar mean ± SD amounts of time providing direct patient care (PCPs-adults: 94.66% ± 8.4%, psychiatrists: 91.15% ± 12.2%). Based on composite scores, BED knowledge increased from wave 1 to wave 2 in PCPs-adults (P < .001) and psychiatrists (P < .05). Composite scores pertaining to knowledge of and comfort with diagnosing and treating BED were lower for PCPs-adults than psychiatrists in both waves (all P < .001). Based on wave 2 responses, the BEDS-7 was used by 32.0% of PCPs-adults and 26.8% of psychiatrists. All BEDS-7 users (100%) indicated the screener was "very" or "somewhat" valuable, and nearly all users (psychiatrists: 100%, PCPs-adults: 97.4%) reported it was "very" or "reasonably" easy to use. BEDS-7 users reported that important uses of the screener included assisting clinicians in identifying BED patients and encouraging/initiating doctor-patient discussions about BED.

Conclusions: These results support the utility of the BEDS-7 in clinical practice, with BEDS-7 users reporting that it is a highly valued and easy-to-use screener. Furthermore, both PCPs-adults and psychiatrists acknowledged the importance of being knowledgeable about BED.
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http://dx.doi.org/10.4088/PCC.16m02075DOI Listing
June 2017

Estimating the Proportion of Childhood Cancer Cases and Costs Attributable to the Environment in California.

Am J Public Health 2017 May 21;107(5):756-762. Epub 2017 Mar 21.

Lauren Nelson is with the California Epidemiologic Investigation Service Fellowship Program, California Department of Public Health, Richmond. Jhaqueline Valle, Galatea King, Maxwell J. Richardson, and Eric M. Roberts are with the California Environmental Health Tracking Program, Richmond. Paul K. Mills is with the Fresno Medical Education and Research Program, University of California San Francisco, Fresno. Daniel Smith and Paul English are with the California Department of Public Health, Richmond.

Objectives: To estimate the proportion of cases and costs of the most common cancers among children aged 0 to 14 years (leukemia, lymphoma, and brain or central nervous system tumors) that were attributable to preventable environmental pollution in California in 2013.

Methods: We conducted a literature review to identify preventable environmental hazards associated with childhood cancer. We combined risk estimates with California-specific exposure prevalence estimates to calculate hazard-specific environmental attributable fractions (EAFs). We combined hazard-specific EAFs to estimate EAFs for each cancer and calculated an overall EAF. Estimated economic costs included annual (indirect and direct medical) and lifetime costs.

Results: Hazards associated with childhood cancer risks included tobacco smoke, residential exposures, and parental occupational exposures. Estimated EAFs for leukemia, lymphoma, and brain or central nervous system cancer were 21.3% (range = 11.7%-30.9%), 16.1% (range = 15.0%-17.2%), and 2.0% (range = 1.7%-2.2%), respectively. The combined EAF was 15.1% (range = 9.4%-20.7%), representing $18.6 million (range = $11.6 to $25.5 million) in annual costs and $31 million in lifetime costs.

Conclusions: Reducing environmental hazards and exposures in California could substantially reduce the human burden of childhood cancer and result in significant annual and lifetime savings.
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http://dx.doi.org/10.2105/AJPH.2017.303690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388954PMC
May 2017

Longitudinal Modeling Approaches to Assess the Association Between Changes in 2 Clinical Outcome Assessments.

Ther Innov Regul Sci 2018 05 26;52(3):306-312. Epub 2017 Sep 26.

1 RTI Health Solutions, Research Triangle Park, NC, USA.

Background: Understanding how one clinical outcome assessment (COA) (eg, a patient-reported outcome [PRO]) relates to a second COA (eg, a clinician-reported outcome [ClinRO]) may provide insights into disease burden or treatment efficacy. We aimed to briefly review commonly used cross-sectional methods to evaluate the association between a PRO and a ClinRO and to demonstrate the advantages of longitudinal modeling approaches, particularly a joint mixed model for repeated measures (MMRM), to evaluate this association.

Methods: We generated an example longitudinal data set that included a PRO measured on an 11-point numeric rating scale and a binary ClinRO. The association between change in PRO score and ClinRO response at each time point was examined using 2 cross-sectional analyses: point biserial correlation and logistic regression. We conducted longitudinal analyses of the association between the 2 COAs across time points using MMRM and joint MMRM approaches.

Results: Point-biserial correlation and logistic regression analyses correctly captured the "built in" associations between the 2 COAs that strengthened over time, but each association was applicable only for a single time point. The MMRM approach provided correlations over time but only for a single outcome variable. The joint MMRM approach modeled the relationship between both outcome variables simultaneously, allowing for evaluation of the correlations both within and between the variables over time.

Conclusion: Each analysis demonstrated the relationship between PRO score changes and ClinRO response. Longitudinal analysis methods, particularly the joint MMRM, allow for a more thorough examination of the correlations among the 2 outcomes than cross-sectional analysis methods.
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http://dx.doi.org/10.1177/2168479017731584DOI Listing
May 2018

Health Status of Patients with Moderate to Severe COPD after Treatment with Nebulized Arformoterol Tartrate or Placebo for 1 Year.

Clin Ther 2017 Jan 20;39(1):66-74. Epub 2016 Dec 20.

RTI Health Solutions, Research Triangle Park, North Carolina.

Purpose: Chronic obstructive pulmonary disease (COPD) is a progressive disease that impairs both objectively measured lung function and patient-reported health status. In a randomized clinical trial of patients with moderate to severe COPD, we compared changes in health status after adding arformoterol tartrate or placebo to patients' treatment regimens.

Methods: In this multicenter, double-blind trial, patients were randomized to receive nebulized arformoterol 15 µg BID (n = 420) or matched placebo (n = 421). Treatment with other COPD medications was permitted, except for long-acting β-agonists. Inclusion criteria were a forced expiratory volume in 1 second (FEV) ≤65% of predicted, FEV >0.50 L, age ≥40 years, smoking history ≥15 pack-years, and a baseline breathlessness severity grade ≥2. The Clinical COPD Questionnaire (CCQ) was used to measure health status at randomization and at months 3, 6, and 12. CCQ scores range from 0 to 6, with higher scores indicating worse health status, and a decrease from baseline in total score by 0.4 point is considered clinically significant. Outcomes were analyzed by using mixed models for repeated measures.

Findings: At baseline, patients' mean age was 63.8 years; 42.9% of patients were female, and 51.4% were current smokers. The mean baseline CCQ total scores were 2.88 and 2.91 for the arformoterol and placebo groups, respectively. A total of 841 patients were randomized to receive either arformoterol (n = 420) or placebo (n = 421); among them, 211 (50.1%) who received placebo and 255 (60.7%) who received arformoterol completed the trial. Arformoterol-treated patients had greater mean improvement from baseline in CCQ total score (-0.18 vs 0.02; P = 0.001), symptoms (-0.21 vs 0.01; P = 0.002), functional state (-0.15 vs 0.02; P = 0.018), and mental state (-0.18 vs 0.02; P = 0.023) than patients receiving placebo. At study end, 38.3% of the arformoterol-treated patients and 30.8% of patients receiving placebo reported clinically significant improvements on the CCQ (P = 0.026). These improvements were only modestly correlated with improvements in FEV (r = -0.15; P < 0.01).

Implications: In this 52-week trial, arformoterol-treated patients had greater improvements in health status than patients receiving placebo. Assessing health status along with lung function seems to provide additional information regarding the effectiveness of COPD maintenance treatments. ClinicalTrials.gov identifier: NCT00909779.
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http://dx.doi.org/10.1016/j.clinthera.2016.11.021DOI Listing
January 2017

Regional anesthesia or patient-controlled analgesia and compartment syndrome in orthopedic surgical procedures: a systematic review.

Local Reg Anesth 2016 6;9:65-81. Epub 2016 Oct 6.

Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL.

A systematic review of the literature on the use of regional anesthesia (RA) and patient-controlled analgesia (PCA) was conducted in patients who require orthopedic extremity procedures to determine whether either analgesic technique contributes to a delayed diagnosis of compartment syndrome (CS). A total of 34 relevant articles (28 case reports and six research articles) were identified. Of all case report articles published after 2009, the majority (75%) concluded that RA does not put the patient at an increased risk of a delayed diagnosis of CS. Of these, only two relevant prospective research studies focusing on RA or PCA and their relationship to CS were identified. Neither study resulted in any cases of CS. However, both had relatively small sample sizes. Given the lack of evidence identified in this systematic review, prospective studies or large-scale retrospective data reviews are needed to more strongly advocate the use of one modality of analgesia over the other in this patient population.
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http://dx.doi.org/10.2147/LRA.S109659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063486PMC
October 2016

Development of the 7-Item Binge-Eating Disorder Screener (BEDS-7).

Prim Care Companion CNS Disord 2016 28;18(2). Epub 2016 Apr 28.

RTI Health Solutions, Durham, North Carolina.

Objective: Develop a brief, patient-reported screening tool designed to identify individuals with probable binge-eating disorder (BED) for further evaluation or referral to specialists.

Methods: Items were developed on the basis of the DSM-5 diagnostic criteria, existing tools, and input from 3 clinical experts (January 2014). Items were then refined in cognitive debriefing interviews with participants self-reporting BED characteristics (March 2014) and piloted in a multisite, cross-sectional, prospective, noninterventional study consisting of a semistructured diagnostic interview (to diagnose BED) and administration of the pilot Binge-Eating Disorder Screener (BEDS), Binge Eating Scale (BES), and RAND 36-Item Short-Form Health Survey (RAND-36) (June 2014-July 2014). The sensitivity and specificity of classification algorithms (formed from the pilot BEDS item-level responses) in predicting BED diagnosis were evaluated. The final algorithm was selected to minimize false negatives and false positives, while utilizing the fewest number of BEDS items.

Results: Starting with the initial BEDS item pool (20 items), the 13-item pilot BEDS resulted from the cognitive debriefing interviews (n = 13). Of the 97 participants in the noninterventional study, 16 were diagnosed with BED (10/62 female, 16%; 6/35 male, 17%). Seven BEDS items (BEDS-7) yielded 100% sensitivity and 38.7% specificity. Participants correctly identified (true positives) had poorer BES scores and RAND-36 scores than participants identified as true negatives.

Conclusions: Implementation of the brief, patient-reported BEDS-7 in real-world clinical practice is expected to promote better understanding of BED characteristics and help physicians identify patients who may have BED.
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http://dx.doi.org/10.4088/PCC.15m01896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956427PMC
February 2017

Psychometric validation of the depression and family functioning scale.

Curr Med Res Opin 2016 25;32(4):639-50. Epub 2016 Jan 25.

e Hospital Ste Marguerite , CHU Marseille , France.

Objective: A new patient-reported outcome (PRO) measure developed to assess the impact of major depressive disorder (MDD) on partner and family interactions and quality of relationships, the Depression and Family Functioning Scale (DFFS), was analyzed to establish its reliability, validity, and responsiveness.

Methods: Data from a multi-center, prospective, 2-year observational study were analyzed to assess the psychometric properties of the DFFS in patients with MDD (nBaseline = 478; nMonth2 = 433). Measures administered to assess validity included the Sheehan Disability Scale (SDS), Arizona Sexual Experiences Scale (ASEX) and Short Form Health Survey-12 (SF-12). Reliability (Cronbach's alphas and intra-class correlations), construct validity (factor analysis and correlations), discriminating ability (analyses of variance), and responsiveness (standardized effect size estimates) were evaluated.

Results: Principal components analyses indicated a single underlying dimension, confirmed by highly satisfactory Cronbach's alphas (αBaseline = 0.85, αMonth2 = 0.89). The DFFS demonstrated satisfactory test-re-test reliability in patients with the same SDS family life/home responsibilities ratings at baseline and month 2 (intraclass correlation = 0.75). Correlations with other measures showed convergent and divergent validity; e.g., the DFFS correlated better with SF-12 mental component scores (rBaseline = -0.35, rMonth2 = -0.49) than with SF-12 physical component scores (rBaseline = -0.05, rMonth2 = -0.31). Hypothesis tests were generally as predicted; many were statistically significant, substantiating DFFS discriminating ability. Standardized effect size estimates of responsiveness ranged from 0.44-0.84, demonstrating that the items were capable of detecting change.

Conclusions: The psychometric analyses support the reliability, validity, and responsiveness of the DFFS and its usefulness for assessing the impact of depression on family functioning. The DFFS can potentially provide important information not captured in clinical practice and facilitate more comprehensive evaluation of MDD treatments.
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http://dx.doi.org/10.1185/03007995.2015.1135111DOI Listing
December 2016

Psychometric validation of the Psoriasis Symptom Diary using Phase III study data from patients with chronic plaque psoriasis.

Int J Dermatol 2016 Mar 30;55(3):e147-55. Epub 2015 Oct 30.

Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Objectives: This analysis aimed to confirm the reliability, validity, and responsiveness of the Psoriasis Symptom Diary (PSD) using data from two Phase III studies in patients with moderate to severe chronic plaque psoriasis.

Methods: Data from two randomized, double-blind, double-dummy, placebo-controlled, multicenter Phase III studies (n = 820) assessing the efficacy and safety of secukinumab were used. The PSD (24-h recall; 0-10 numeric rating scale) was electronically administered each evening. Test-retest reliability was determined using intraclass correlations. Construct validity hypotheses were evaluated via correlations with the Psoriasis Area and Severity Index (PASI), Investigator's Global Assessment (IGA), Dermatology Life Quality Index (DLQI), EuroQoL 5-Dimension Health Status Questionnaire, and Patient Global Impression of Change (PGIC). Discriminating ability and responsiveness were evaluated by estimating mean differences and effect sizes between known groups (using the PASI and IGA). Phase II-derived, anchor-based PGIC thresholds and cumulative distribution function (CDF) plots described meaningful change.

Results: Items on the PSD yielded high intraclass coefficients (>0.90). Correlations were in the anticipated direction and by week 12 were moderate to strong (0.41-0.73) in magnitude, demonstrating construct validity. Average PSD item scores differed predictably and significantly between known groups. Responsiveness effect size estimates were moderate to large (0.6-1.5), and CDF plots showed the percentage of responders to be consistently higher in treatment than in placebo arms across the range of change in PSD scores.

Conclusions: The PSD is reliable, valid, and responsive, and represents a valid tool to enhance treatment decisions in patients with moderate to severe plaque psoriasis.
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http://dx.doi.org/10.1111/ijd.13117DOI Listing
March 2016

Advances in the Evaluation of Longitudinal Construct Validity of Clinical Outcome Assessments.

Ther Innov Regul Sci 2015 Nov;49(6):805-812

1 RTI Health Solutions, Research Triangle Park, NC, USA.

Historically, the assessment of longitudinal construct validity in the field of psychosocial measurement involved defining hypotheses and calculating correlation coefficients using scores based on 2 measures at 2 or more time points. In the context of patient-reported outcomes, this evolved into sensitivity to change and responsiveness, including the computation of effect size estimates of change, standardized response means, and indices such as Guyatt's statistic. Cross-sectional analyses or analyses based on 2 time points have been the standard practice. Evolving conceptualizations have incorporated more than 2 time points and have included depictions of individual trajectories of change in multiple measures, structural equation models, and mixed modeling techniques. The focus of this article is on methods to evaluate longitudinal construct validity. We describe a sample of these methods and provide considerations and recommendations for designing a thoughtful longitudinal construct validity evaluation of clinical outcome assessments.
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http://dx.doi.org/10.1177/2168479015609103DOI Listing
November 2015

Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C.

United European Gastroenterol J 2015 Feb;3(1):53-62

Ironwood Pharmaceuticals, Cambridge, MA, USA.

Background: Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain.

Objective: The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms.

Methods: Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed.

Results: Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48-0.54, 0.32-0.39, and 0.61-0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS-C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%-76% and 71%-82% of weeks with agreement, respectively).

Conclusions: AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.
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http://dx.doi.org/10.1177/2050640614555946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315678PMC
February 2015

Development and validation of the ADHD Benefits of Coaching Scale (ABCS).

J Atten Disord 2015 Mar 4;19(3):191-9. Epub 2014 Dec 4.

RTI Health Solutions, Research Triangle Park, NC, USA.

Objective: Develop and validate the ADHD Benefits of Coaching Scale (ABCS), a self-report instrument designed to measure benefits of ADHD coaching in college students.

Method: Concepts were elicited from interviews with ADHD coaches and college students receiving ADHD coaching. Draft items were tested in cognitive interviews among ADHD students. Item and scale reliability and validity of ABCS were evaluated using web-survey data from students reporting ADHD. Mean ABCS scores for coached and noncoached groups were compared.

Results: Five coaches and 14 students participated in concept elicitation interviews; 10 students participated in the cognitive interviews; 209 students completed the web-survey. The 10-item ABCS showed satisfactory internal consistency reliability and validity and differentiated between coached (n = 17) and noncoached groups (n = 192; p < .01).

Conclusion: To assess benefits of ADHD coaching in college students, the ABCS was developed and psychometrically validated in accordance with Food and Drug Administration's (FDA) patient-reported outcome guidance.
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http://dx.doi.org/10.1177/1087054714558118DOI Listing
March 2015

Psychometric validation of patient-reported outcome measures assessing chronic constipation.

Clin Exp Gastroenterol 2014 26;7:385-94. Epub 2014 Sep 26.

Ironwood Pharmaceuticals, Cambridge, MA, USA.

Background: Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration's guidance on patient-reported outcomes.

Aim: Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures.

Study Methods: Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed.

Results: The CC Symptom Severity Measures demonstrated satisfactory test-retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change.

Conclusion: In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.
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http://dx.doi.org/10.2147/CEG.S64713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186570PMC
October 2014

Treatment effectiveness of pasireotide on health-related quality of life in patients with Cushing's disease.

Eur J Endocrinol 2014 Jul 23;171(1):89-98. Epub 2014 Apr 23.

Department of Medicine/EndocrinologyCentre for Biomedical Research on Rare Diseases (CIBERER Unit 747), Hospital Sant Pau, Universitat Autònoma de Barcelona, Barcelona, SpainDepartment of Quantitative Health SciencesUniversity of Massachusetts Medical School, Worcester, Massachusetts, USAJohn Ware Research GroupInc., Worcester, Massachusetts, USANovartis Pharmaceuticals CorporationEast Hanover, New Jersey, USAAnalysis GroupInc., Boston, Massachusetts, USAIMS HealthBarcelona, SpainRTI Health SolutionsResearch Triangle Park, North Carolina, USANovartis Pharma AGBasel, SwitzerlandDepartment of EndocrinologyCentre for Postgraduate Medical Education, Warsaw, PolandDepartment of EndocrinologyDiabetology and Metabolism, University Hospital, Antwerp, BelgiumNational Institute of Neurology and Neurosurgery 'Manuel Velasco Suárez'Mexico City, MexicoDivision of EndocrinologyMedical School, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Objective: Cushing's disease (CD) can significantly impair patients' health-related quality of life (HRQOL). This study investigated the treatment effectiveness of pasireotide on HRQOL of CD patients, and assessed the relationships between HRQOL and urinary free cortisol (UFC) and CD-related signs and symptoms.

Design: In this phase III, randomized, double-blind study, patients with UFC ≥1.5×upper limit of normal (ULN) received s.c. pasireotide 600 or 900 μg twice daily. The trial primary endpoint was UFC at or below ULN at month 6 without dose titration. Open-label treatment continued through month 12. HRQOL was measured using the Cushing's Quality of Life Questionnaire (CushingQoL) instrument at baseline and follow-up visits until month 12 during which clinical signs and features of CD, and the Beck Depression Inventory II (BDI-II), were also collected.

Methods: Pearson's/Spearman's correlations between changes in CushingQoL and changes in clinical signs and symptoms were assessed. Changes in CushingQoL and the proportion of patients achieving a clinically meaningful improvement in CushingQoL were also compared among patients stratified by mean UFC (mUFC) control status (controlled, partially controlled, and uncontrolled) at month 6. Analyses were also conducted at month 12, with multivariable adjustment for baseline characteristics and CushingQoL.

Results: Change in CushingQoL was significantly correlated with changes in mUFC (r=-0.40), BMI (r=-0.39), weight (r=-0.41), and BDI-II (r=-0.54) at month 12 but not at month 6. The percentage of CushingQoL responders at month 12 based on month 6 mUFC control status were as follows: 63, 58.8, and 37.9% in the controlled, partially controlled, and uncontrolled groups respectively. Adjusted CushingQoL scores at month 12 were 58.3 for controlled patients (Δ=11.5 vs uncontrolled, P=0.012) and 54.5 for partially controlled patients (Δ=7.7 vs uncontrolled, P=0.170).

Conclusions: Pasireotide treatment can result in a meaningful HRQOL improvement among those who complete a 12-month treatment period, most often among patients achieving biochemical control.
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http://dx.doi.org/10.1530/EJE-13-1013DOI Listing
July 2014