Development of the Near Vision Presbyopia Task-based Questionnaire for use in evaluating the impact of presbyopia.

BACKGROUND: Presbyopia is a progressive condition that reduces the eye's ability to focus on near objects with increasing age. After a systematic literature review identified no existing presbyopia-specific patient-reported outcome (PRO) instruments meeting regulatory guidance, a new PRO instrument, the Near Vision Presbyopia Task-based Questionnaire (NVPTQ), was developed. RESULTS: To explore the patient experience with presbyopia, concept elicitation interviews were conducted with 20 presbyopic participants. The most frequently reported impacts were difficulty with reading menus/books/newspapers/magazines, reading on a cell phone/caller ID, and reading small print. Based on these results, a task-based PRO instrument (the NVPTQ) was developed instructing participants to complete four near-vision, paper-based reading tasks (book, newspaper, nutrition label, menu) under standardized settings, and subsequently assess their vision-related reading ability and associated satisfaction. The draft NVPTQ was cognitively debriefed with a sample of 20 presbyopes, which demonstrated that most participants interpreted the items as intended and endorsed the relevance of the concepts being assessed. After the qualitative research, the draft instrument was psychometrically tested using data from a Phase 2 study. Based on item-level analyses, all items in the NVPTQ demonstrated expected response option patterns and lacked substantial floor or ceiling effects. The reliability, validity, and responsiveness of the NVPTQ Performance and Satisfaction domain scores were assessed. All domains scores had large Cronbach's coefficient α values and good test-retest statistics, indicating that the scores are internally consistent and produce stable values over time. The pattern of correlations with a concurrent measure of visual functioning (National Eye Institute Visual Function Questionnaire 25) demonstrated that the NVPTQ domain scores were related to an alternative assessment of near-vision activities. The NVPTQ domain scores were able to distinguish between groups that were known to differ on the clinical outcome of uncorrected near visual acuity, supporting the construct validity of these scores. The NVPTQ domain scores showed evidence of responsiveness to change by being able to distinguish between groups defined as improved and not improved based on patient-reported and clinical outcomes. CONCLUSIONS: This research has resulted in a content-valid and psychometrically sound instrument designed to evaluate vision-related reading ability and satisfaction with vision-related reading ability. TRIAL REGISTRATION: ClinicalTrials.gov NCT02780115. Registered 23 May 2016, https://www.clinicaltrials.gov/ct2/show/NCT02780115?term=NCT02780115&draw=2&rank=1.

Development of the Presbyopia Impact and Coping Questionnaire.

INTRODUCTION: Presbyopia is a progressive, age-related visual condition that is characterized by reduced ability to focus on near/close objects, causing impacts on individuals' daily function and health-related quality of life. The Presbyopia Impact and Coping Questionnaire (PICQ) is a new patient-reported outcome (PRO) instrument that assesses presbyopia impact and use of coping behaviors among presbyopic individuals. METHODS: To document the impacts of presbyopia and associated coping behaviors, concept elicitation (CE) interviews were conducted with 20 presbyopic participants. Results from the CE interviews were used to develop draft items for additional testing. Following item generation, the draft PICQ was cognitively debriefed with 20 participants. Data from a phase 2 controlled clinical trial were used for psychometric analyses of the PICQ. The PICQ was administered at site visits throughout a 28-day treatment period. Confirmatory factor analysis (CFA) methods were used to guide the development of the scoring algorithm. The reliability (internal consistency, test-retest), construct validity (convergent and discriminant validity, known-groups methods), and responsiveness (Guyatt's responsiveness statistic [GRS]) of the PICQ scores were evaluated. Finally, anchor-based and distribution-based methods were used to inform thresholds for interpreting meaningful within-patient change. RESULTS: CE interviews identified the important and relevant presbyopia-related impacts and coping behaviors and 22 items were drafted and cognitively debriefed. Following minor revisions and item addition/deletion, a version of the PICQ including 23 items was subjected to psychometric testing. The analysis sample included 151 participants. The CFA established two PICQ domain scores, Coping and Impact, on 0-to-4 scales that demonstrate good model fit (root mean square error of approximation = 0.06, comparative fit index = 0.98, Tucker-Lewis index = 0.98, standardized root mean square = 0.07). Cronbach's alphas for the Coping and Impact scores were 0.89 and 0.84, respectively. Test-retest intraclass correlation coefficients were 0.77 for Coping and 0.67 for Impact. The pattern of results assessing construct validity was acceptable for the PICQ Coping and Impact scores, with the magnitude of correlations and effect sizes generally meeting a priori expectations. The corresponding GRS effect sizes for the PICQ Coping scores were -1.23 (i.e., large) for Patient Global Impression of Change (PGIC) and -0.72 (i.e., medium) for uncorrected near visual acuity (UNVA). The GRS effect sizes for the PICQ Impact scores were -0.60 (i.e., medium) for PGIC and -0.35 (i.e., small) for UNVA. Across three sets of anchor-based analyses for interpreting individual-level change, a responder threshold of -1.00 was identified for both PICQ Coping and PICQ Impact scores. CONCLUSIONS: The totality of evidence from the qualitative and quantitative research establishes that the PICQ scores produced are valid and reliable measures of presbyopia impacts and coping behaviors that are important and relevant for assessing presbyopia treatment outcomes. CLINICALTRIALS. GOV IDENTIFIER: NCT02780115; date of registration May 19, 2016.

Investigating the formation and diagnostic value of ω-(o-alkylphenyl)alkanoic acids in ancient pottery.

Long-chain ω-(o-alkylphenyl)alkanoic acids (APAAs) derived from the heating of unsaturated fatty acids have been widely used for the identification of aquatic products in archaeological ceramic vessels. To date, little attention has been paid to the diagnostic potential of shorter chain (< C20) APAAs, despite their frequent occurrence. Here, a range of laboratory and field experiments and analyses of archaeological samples were undertaken to investigate whether APAAs could be used to further differentiate different commodities. The results provide new insights about the conditions for the formation of APAAs and enable the proposition of novel criteria to distinguish different natural products.

Collection of Post-treatment PRO Data in Oncology Clinical Trials.

As patient-reported outcome (PRO) measures are being included more frequently in oncology clinical trials, regulatory and health technology assessment agencies have begun to request long-term, post-treatment PRO data to supplement traditional survival/progression endpoints. These data may be collected as part of cohort extension or registry studies to describe long-term outcomes of study participants after concluding their cancer treatment. While post-treatment PRO data may be expected to satisfy regulatory and payer expectations, significant practical barriers exist for the efficient incorporation of these data into oncology clinical trials, such as subject attrition, protocol deviations, and treatment crossover. The incorporation of post-treatment PRO assessments is a resource-intensive task requiring clear objectives for how the data will be analyzed and interpreted by both sponsors and regulators. Incorporating PRO data collection via electronic modalities (e.g., smartphone, web) may be a less expensive and more feasible option for incorporating long-term follow-up, reducing the frequency of manual study staff follow-up and expensive clinic visits. It is essential to include well-defined estimands for the statistical analysis, as well as to document limitations associated with the long-term follow-up data-collection approach. Analytical techniques will likely rely on descriptive and model-based statistics, and conclusions about treatment differences will likely be limited to preliminary findings of effectiveness (instead of efficacy). Finally, communications with health authorities and regulatory agencies regarding the LTFU study design and analysis should occur as early as possible to ensure that the PRO data to be collected offer an opportunity to properly evaluate the research question(s) of interest.

Agreement Among Paper and Electronic Modes of the EQ-5D-5L.

INTRODUCTION: While the EQ-5D-5L has been migrated to several electronic modes, evidence supporting the measurement equivalence of the original paper-based instrument to the electronic modes is limited. OBJECTIVES: This study was designed to comprehensively examine the equivalence of the paper and electronic modes (i.e., handheld, tablet, interactive voice response [IVR], and web). METHODS: As part of the foundational work for this study, the test-retest reliability of the paper-based, UK English format of the EQ-5D-5L was assessed using a single-group, single-visit, two-period, repeated-measures design. To compare paper and electronic modes, three independent samples were recruited into a three-period crossover study. Each participant was assigned to one of six groups to account for order effects. Descriptive statistics, mean differences (i.e., split-plot analysis of variance [ANOVA]), and intraclass correlation coefficients (ICCs) were calculated. RESULTS: The test-retest results showed mean differences near zero and ICC values > 0.90 for both the index and the EQ VAS scores. For the electronic comparisons, mean difference confidence intervals (CIs) for the EQ-5D index scores and EQ VAS scores reflected equivalence of the means across all modes, as the CIs were wholly contained inside the equivalence interval. Further, the ICC 95% lower CIs for the index and EQ VAS scores showed values above the thresholds for denoting equivalence across all comparisons in each sample. No significant mode-by-order interactions were present in any ANOVA model. CONCLUSIONS: Overall, our comparisons of the paper, screen-based, and phone-based formats of the EQ-5D-5L provided substantial evidence to support the measurement equivalence of these modes of data collection.

Psychometric Analysis of the Abdominal Score From the Diary for Irritable Bowel Syndrome Symptoms-Constipation Using Phase IIb Clinical Trial Data.

OBJECTIVES: The Diary for Irritable Bowel Syndrome Symptoms-Constipation (DIBSS-C) has been developed to assess the core signs and symptoms of irritable bowel syndrome with constipation (IBS-C). This article presents the psychometric evaluation of the DIBSS-C abdominal score. METHODS: Data for these analyses are from a multicenter phase IIb study in IBS-C patients (NCT02559206). Subjects completed a number of assessments via handheld electronic diary throughout the study. The analyses used the intent-to-treat population and were blinded to randomized treatment group. The analyses evaluated the reliability, validity, and responsiveness of the DIBSS-C abdominal score; identified an appropriate scoring algorithm; and determined thresholds for interpreting clinically meaningful changes at the individual level. RESULTS: The correlations between the DIBSS-C abdominal symptom items (ie, abdominal pain, discomfort, and bloating) were strong (>0.75). Cronbach's alpha for the abdominal symptom severity items was very strong (.94), indicating that the 3 abdominal symptom items produce a reliable score. The intraclass correlation coefficient for the abdominal score was 0.82, exceeding the threshold of 0.70 and indicating good test-retest reliability. Guyatt's responsiveness statistic values all exceeded the threshold for a large effect of 0.80, so the DIBSS-C abdominal score can be considered highly responsive to change. Triangulation across 3 sets of anchor-based analyses indicated that a threshold of -2.0 points on the abdominal score is an appropriate threshold for identifying meaningful change. CONCLUSIONS: Overall, this study provides evidence that the DIBSS-C abdominal score is valid, reliable, responsive to change, and interpretable for assessing treatment benefit in patients with IBS-C.

Physical Frailty: ICFSR International Clinical Practice Guidelines for Identification and Management.

OBJECTIVE: The task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults. METHODS: These recommendations were formed using the GRADE approach, which ranked the strength and certainty (quality) of the supporting evidence behind each recommendation. Where the evidence-base was limited or of low quality, Consensus Based Recommendations (CBRs) were formulated. The recommendations focus on the clinical and practical aspects of care for older people with frailty, and promote person-centred care. Recommendations for Screening and Assessment: The task force recommends that health practitioners case identify/screen all older adults for frailty using a validated instrument suitable for the specific setting or context (strong recommendation). Ideally, the screening instrument should exclude disability as part of the screening process. For individuals screened as positive for frailty, a more comprehensive clinical assessment should be performed to identify signs and underlying mechanisms of frailty (strong recommendation). Recommendations for Management: A comprehensive care plan for frailty should address polypharmacy (whether rational or nonrational), the management of sarcopenia, the treatable causes of weight loss, and the causes of exhaustion (depression, anaemia, hypotension, hypothyroidism, and B12 deficiency) (strong recommendation). All persons with frailty should receive social support as needed to address unmet needs and encourage adherence to a comprehensive care plan (strong recommendation). First-line therapy for the management of frailty should include a multi-component physical activity programme with a resistance-based training component (strong recommendation). Protein/caloric supplementation is recommended when weight loss or undernutrition are present (conditional recommendation). No recommendation was given for systematic additional therapies such as cognitive therapy, problem-solving therapy, vitamin D supplementation, and hormone-based treatment. Pharmacological treatment as presently available is not recommended therapy for the treatment of frailty.

International Clinical Practice Guidelines for Sarcopenia (ICFSR): Screening, Diagnosis and Management.

OBJECTIVES: Sarcopenia, defined as an age-associated loss of skeletal muscle function and muscle mass, occurs in approximately 6 - 22 % of older adults. This paper presents evidence-based clinical practice guidelines for screening, diagnosis and management of sarcopenia from the task force of the International Conference on Sarcopenia and Frailty Research (ICSFR). METHODS: To develop the guidelines, we drew upon the best available evidence from two systematic reviews paired with consensus statements by international working groups on sarcopenia. Eight topics were selected for the recommendations: (i) defining sarcopenia; (ii) screening and diagnosis; (iii) physical activity prescription; (iv) protein supplementation; (v) vitamin D supplementation; (vi) anabolic hormone prescription; (vii) medications under development; and (viii) research. The ICSFR task force evaluated the evidence behind each topic including the quality of evidence, the benefit-harm balance of treatment, patient preferences/values, and cost-effectiveness. Recommendations were graded as either strong or conditional (weak) as per the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Consensus was achieved via one face-to-face workshop and a modified Delphi process. RECOMMENDATIONS: We make a conditional recommendation for the use of an internationally accepted measurement tool for the diagnosis of sarcopenia including the EWGSOP and FNIH definitions, and advocate for rapid screening using gait speed or the SARC-F. To treat sarcopenia, we strongly recommend the prescription of resistance-based physical activity, and conditionally recommend protein supplementation/a protein-rich diet. No recommendation is given for Vitamin D supplementation or for anabolic hormone prescription. There is a lack of robust evidence to assess the strength of other treatment options.

Assessing Asthma Symptoms in Adolescents and Adults: Qualitative Research Supporting Development of the Asthma Daily Symptom Diary.

BACKGROUND: Despite the widespread availability of patient-reported asthma questionnaires, instruments developed in accordance with present regulatory expectations are lacking. To address this gap, the Patient-Reported Outcome (PRO) Consortium's Asthma Working Group has developed a patient-reported asthma daily symptom diary (ADSD) for use in clinical research to assess outcomes and support medical product labeling claims in adults and adolescents with asthma. OBJECTIVES: To summarize the qualitative research conducted to inform the initial development of the ADSD and to provide evidence for content validity of the instrument in accordance with the Food and Drug Administration's PRO Guidance. METHODS: Research informing the initial development and confirming the content validity of the ADSD is summarized. This comprised a review of published qualitative research, semi-structured concept elicitation interviews (n = 55), and cognitive interviews (n = 65) with a diverse and representative sample of adults and adolescents with a clinician-confirmed diagnosis of asthma in the United States to understand the asthma symptom experience and to assess the relevance and understanding of the newly developed ADSD. RESULTS: From the qualitative literature review and concept elicitation interviews, eight core asthma symptoms emerged. These were broadly categorized as breathing symptoms (difficulty breathing, shortness of breath, and wheezing), chest symptoms (chest tightness, chest pain, and pressure/weight on chest), and cough symptoms (cough and the presence of mucus/phlegm). Conceptual saturation was achieved and differences in the experience of participants according to socio-demographic or clinical characteristics were not observed. Subsequent testing of the ADSD confirmed participant relevance and understanding. CONCLUSIONS: The ADSD is a new patient-reported asthma symptom diary developed in accordance with the Food and Drug Administration's PRO Guidance. Evidence to date supports the content validity of the instrument. Item performance, reliability, and construct validity will be assessed in future quantitative research.

Development of a Symptom-Based Patient-Reported Outcome Instrument for Functional Dyspepsia: A Preliminary Conceptual Model and an Evaluation of the Adequacy of Existing Instruments.

OBJECTIVES: The aim was to document, from the perspective of the empirical literature, the primary symptoms of functional dyspepsia (FD), evaluate the extent to which existing questionnaires target those symptoms, and, finally, identify any missing evidence that would impact the questionnaires' use in regulated clinical trials to assess treatment efficacy claims intended for product labeling. METHODS: A literature review was conducted to identify the primary symptoms of FD and existing symptom-based FD patient-reported outcome (PRO) instruments. Following a database search, abstracts were screened and articles were retrieved for review. The primary symptoms of FD were organized into a conceptual model and the PRO instruments were evaluated for conceptual coverage as well as compared against evidentiary requirements presented in the FDA's PRO Guidance for Industry. RESULTS: Fifty-six articles and 16 instruments assessing FD symptoms were reviewed. Concepts listed in the Rome III criteria for FD (n = 7), those assessed by existing FD instruments (n = 34), and symptoms reported by patients in published qualitative research (n = 6) were summarized in the FD conceptual model. Except for vomiting, all of the identified symptoms from the published qualitative research reports were also specified in the Rome III criteria. Only three of the 16 instruments, the Dyspepsia Symptom Severity Index (DSSI), Nepean Dyspepsia Index (NDI), and Short-Form Nepean Dyspepsia Index (SF-NDI), measure all seven FD symptoms defined by the Rome III criteria. Among these three, each utilizes a 2-week recall period and 5-point Likert-type scale, and had evidence of patient involvement in development. Despite their coverage, when these instruments were evaluated in light of regulatory expectations, several issues jeopardized their potential qualification for substantiation of a labeling claim. CONCLUSIONS: No existing PRO instruments that measured all seven symptoms adhered to the regulatory principles necessary to support product labeling. As such, the development of a new FD symptom PRO instrument is supported.

A Systematic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies.

BACKGROUND: The muscular dystrophies are a heterogeneous group of genetic muscle diseases with variable distribution of weakness and mode of inheritance. METHODS: We previously performed a systematic review of worldwide population-based studies on Duchenne and Becker muscular dystrophies; the current study focused on the epidemiology of other muscular dystrophies using Medline and EMBASE databases. Two reviewers independently reviewed all abstracts, full-text articles, and abstracted data from 1985 to 2011. Pooling of prevalence estimates was performed using random-effect models. RESULTS: A total of 1104 abstracts and 167 full-text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The overall pooled prevalence of combined muscular dystrophies was 16.14 (confidence interval [CI], 11.21-23.23) per 100,000. The prevalence estimates per 100,000 were 8.26 (CI, 4.99-13.68) for myotonic dystrophy, 3.95 (CI, 2.89-5.40) for facioscapulohumeral dystrophy, 1.63 (CI, 0.94-2.81) for limb girdle muscular dystrophy, and 0.99 (CI, 0.62-1.57) for congenital muscular dystrophies. CONCLUSIONS: The studies differed widely in their approaches to case ascertainment, and substantial gaps remain in the global estimates of many other types of muscular dystrophies. Additional epidemiological studies using standardized diagnostic criteria as well as multiple sources of case ascertainment will help address the economic impact and health care burden of muscular dystrophies worldwide.

Development of a patient-reported outcome instrument to assess complex activities of daily living and interpersonal functioning in persons with mild cognitive impairment: The qualitative research phase.

INTRODUCTION: As drug development research efforts move toward studying patients earlier in the course of Alzheimer's disease (AD), it is important to incorporate the patient's perspective into measurement of outcomes. METHODS: This article summarizes the qualitative work of the Patient-Reported Outcome Consortium's Cognition Working Group in the development of a new self-reported outcome measure in persons with mild cognitive impairment (MCI) due to suspected AD, herein referred to as MCI. RESULTS: The draft measure captures the patient's voice for two functional domains, complex activities of daily living and interpersonal functioning. DISCUSSION: This work represents a series of initial steps in the development of this rating scale. The next steps are to conduct psychometric analysis and evaluate the role of insight.

Considerations for Requiring Subjects to Provide a Response to Electronic Patient-Reported Outcome Instruments.

The increase in the use of electronic patient-reported outcome (ePRO) instruments has presented study teams with considerations not previously encountered with paper. Specifically, in an effort to minimize missing data, there is now the opportunity of requiring subjects to provide a response to an item before allowing the subject to proceed to the next item. While the ability to require subjects to respond to ePRO items would seem to guarantee a complete data set, it raises questions about the conditions under which it is appropriate to require subjects to respond to the items in an instrument. This article provides guidance on the circumstances under which allowing a subject to opt out of responding to ePRO items may be appropriate. Three main scenarios are discussed: (1) requiring subjects to complete all items in all the instruments in the study, (2) allowing subjects to opt out of at least some selective items that do not support key primary or secondary endpoints, and (3) allowing subjects to opt out of responding to any or all items in the study. For either of the 2 scenarios allowing the subject to opt out of responding to an item, the use of programmed edit checks is highly recommended to confirm that the subject intended to "skip" or "opt out of" the item. This ensures that, at the end of the study, the database contains an explicit data point indicating when a subject has actively decided to skip an item. While this article is focused on patient-reported outcomes, the issues raised could also apply to other clinical outcome assessments, such as clinician- and observer-reported outcomes.

Capturing Patient-Reported Outcome (PRO) Data Electronically: The Past, Present, and Promise of ePRO Measurement in Clinical Trials.

Patient-reported outcomes (PROs) are an important means of evaluating the treatment benefit of new medical products. It is recognized that PRO measures should be used when assessing concepts best known by the patient or best measured from the patient's perspective. As a result, there is growing emphasis on well defined and reliable PRO measures. In addition, advances in technology have significantly increased electronic PRO (ePRO) data collection capabilities and options in clinical trials. The movement from paper-based to ePRO data capture has enhanced the integrity and accuracy of clinical trial data and is encouraged by regulators. A primary distinction in the types of ePRO platforms is between telephone-based interactive voice response systems and screen-based systems. Handheld touchscreen-based devices have become the mainstay for remote (i.e., off-site, unsupervised) PRO data collection in clinical trials. The conventional approach is to provide study subjects with a handheld device with a device-based proprietary software program. However, an emerging alternative for clinical trials is called bring your own device (BYOD). Leveraging study subjects' own Internet-enabled mobile devices for remote PRO data collection (via a downloadable app or a Web-based data collection portal) has become possible due to the widespread use of personal smartphones and tablets. However, there are a number of scientific and operational issues that must be addressed before BYOD can be routinely considered as a practical alternative to conventional ePRO data collection methods. Nevertheless, the future for ePRO data collection is bright and the promise of BYOD opens a new chapter in its evolution.

Strategies for ventilation in acute, severe lung injury after combat trauma.

Post-traumatic Acute Respiratory Distress Syndrome (ARDS) continues to be a major critical care challenge with a high associated mortality and extensive morbidity for those who survive. This paper explores the evolution in recognition and management of this condition and makes some recommendations for treatment of post-combat ARDS for military practitioners. It is aimed at the generalist in disciplines other than critical care, but will also be of interest to intensivists.