Comparing patient global impression of severity and patient global impression of change to evaluate test-retest reliability of depression, non-small cell lung cancer, and asthma measures.

PURPOSE: Score reproducibility is an important measurement property of fit-for-purpose patient-reported outcome (PRO) measures. It is commonly assessed via test-retest reliability, and best evaluated with a stable participant sample, which can be challenging to identify in diseases with highly variable symptoms. To provide empirical evidence comparing the retrospective (patient global impression of change [PGIC]) and current state (patient global impression of severity [PGIS]) approaches to identifying a stable subgroup for test-retest analyses, 3 PRO Consortium working groups collected data using both items as anchor measures. METHODS: The PGIS was completed on Day 1 and Day 8 + 3 for the depression and non-small cell lung cancer (NSCLC) studies, and daily for the asthma study and compared between Day 3 and 10. The PGIC was completed on the final day in each study. Scores were compared using an intraclass correlation coefficient (ICC) for participants who reported "no change" between timepoints for each anchor. RESULTS: ICCs using the PGIS "no change" group were higher for depression (0.84 vs. 0.74), nighttime asthma (0.95 vs. 0.53) and daytime asthma (0.86 vs. 0.68) compared to the PGIC "no change" group. ICCs were similar for NSCLC (PGIS: 0.87; PGIC: 0.85). CONCLUSION: When considering anchor measures to identify a stable subgroup for test-retest reliability analyses, current state anchors perform better than retrospective anchors. Researchers should carefully consider the type of anchor selected, the time period covered, and should ensure anchor content is consistent with the target measure concept, as well as inclusion of both current and retrospective anchor measures.

Real-world outcomes among patients with HER2+ metastatic breast cancer with brain metastases.

BACKGROUND: Among patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC), incidence of brain metastases (BMs) is relatively high and increasing. Despite the high unmet need for patients with HER2+ MBC and BMs, real-world data on treatment patterns and outcomes for these patients are limited. OBJECTIVE: To compare treatment patterns and overall survival (OS) among patients with HER2+ MBC with and without BMs in the United States. METHODS: This was a real-world retrospective cohort study in which adults diagnosed with HER2+ MBC between January 1, 2016, and May 31, 2019, were identified in the Flatiron Health electronic health records database. The cohort was stratified by presence of BMs at MBC diagnosis (baseline) and before the initiation of each line of therapy (LOT). Key outcomes were OS and systemic therapy/regimen used within each LOT. An adjusted Cox proportional hazards model was used to evaluate the impact of BMs on OS. RESULTS: Of 1,755 included patients, 173 (9.9%) had BMs at baseline. Trastuzumab+ pertuzumab-based regimens were the most common first- (n = 689, 44.3%) and second-line (n = 316, 35.3%) treatments for all patients. Among patients with BMs, trastuzumab emtansine was the most common third-line regimen (n = 18, 23.4%). Lapatinib-based regimens were used more frequently among patients with BMs but were used by less than 20% of patients with BMs within any LOT. Median OS was 22.3 and 37.3 months for patients with and without BMs at baseline, respectively. Patients with BMs had a higher risk of death compared with patients without BMs (HR, 3.2; 95% CI = 2.6-3.8). CONCLUSIONS: BMs are associated with an increased risk of mortality among patients with HER2+ MBC. Further studies are needed to evaluate the extent to which novel systemic therapies for HER2+ MBC address the unmet need among patients with BMs. DISCLOSURES: This study was funded by Seagen Inc. Andres Forero-Torres is an employee of and owns stock in Seagen Inc. Kendra DeBusk is an employee of Seagen Inc. and owns stock in Seagen Inc. and Roche. Andy Surinach and Yutong Liu are employees of Genesis Research, which received funding from Seagen Inc. in connection with this study. At the time of this study, Chimeka Ike was an employee of Seagen Inc. and owns stock in Seagen Inc. At the time of this study, Nicolas Lindegger was an employee of Seagen Inc., Seagen International GmbH, and owns stock in Seagen Inc. and Roche. At the time of this study, Naomi Schwartz was a paid consultant to Seagen Inc.; she currently is an employee of and owns stock in Seagen Inc.

Treatment patterns and overall survival in HER2+ metastatic breast cancer at US community oncology practices.

Aim: To describe real-world treatment patterns/outcomes among patients with HER2+ metastatic breast cancer (MBC). Materials & methods: Real-world treatments and overall survival (OS) were evaluated among adult women diagnosed with HER2+ MBC, with and without brain metastases (BMs), between 1 June 2012 and  31 May 2018 using electronic medical records from the Definitive Oncology Dataset. Results: Among 372 patients, 69% initiated first-line trastuzumab plus pertuzumab-based therapy; many therapy combinations were utilized in the second- to fourth-line. During follow-up (median 24.8 months), 18% of patients died (22% with and 16% without BMs). Mean OS was shortest among patients with BMs at MBC diagnosis in the third- and fourth-line. Conclusion: OS was poor, and no clear standard of care was observed among patients with HER2+ MBC progressing on trastuzumab-based therapies.

Non-Small Cell Lung Cancer Symptom Assessment Questionnaire: Psychometric Performance and Regulatory Qualification of a Novel Patient-Reported Symptom Measure.

BACKGROUND: The Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) was developed to incorporate the patient's perspective into evaluation of clinical benefit in advanced non-small cell lung cancer trials and meet regulatory expectations for doing so. Qualitative evidence supported 7 items covering 5 symptom concepts. OBJECTIVE: This study evaluated measurement properties of the NSCLC-SAQ's items, overall scale, and total score. METHODS: In this observational cross-sectional study, a purposive sample of patients with clinician-diagnosed advanced non-small cell lung cancer, initiating or undergoing treatment, provided sociodemographic information and completed the NSCLC-SAQ, National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lung Symptom Index (FLSI-17), and a Patient Global Impression of Severity item. Rasch analyses, factor analyses, and assessments of construct validity and reliability were completed. RESULTS: The 152 participants had a mean age of 64 years, 57% were women, and 87% where White. The majority were Stage IV (83%), 51% had an Eastern Cooperative Oncology Group performance status of 1 (32% performance status 0 and 17% performance status 2), and 33% were treatment naïve. Rasch analyses showed ordered thresholds for response options. Factor analyses demonstrated that items could be combined for a total score. Internal consistency (Cronbach  α = 0.78) and test-retest reliability (intraclass correlation coefficient = 0.87) were quite satisfactory. NSCLC-SAQ total score correlation was 0.83 with the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lung Symptom Index-17. The NSCLC-SAQ was able to differentiate between symptom severity levels and performance status (both P values < .001). CONCLUSIONS: The NSCLC-SAQ generated highly reliable scores with substantial evidence of construct validity. The Food and Drug Administration's qualification supports the NSCLC-SAQ as a measure of symptoms in drug development. Further evaluation is needed on its longitudinal measurement properties and interepretation of meaningful within-patient score change. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).

Efficacy of tucatinib for HER2-positive metastatic breast cancer after HER2-targeted therapy: a network meta-analysis.

Aim: A systematic literature review and network meta-analysis of randomized controlled trials in patients receiving therapy for HER2+ unresectable/metastatic breast cancer after ≥1 HER2-directed therapy was conducted to compare progression-free survival (PFS) and overall survival (OS). Methods: Hazard ratios (HRs) and relative differences from fractional polynomials (FPs) for PFS and OS were assessed by Bayesian network meta-analyses. Results: For PFS, surface under the cumulative rankogram (SUCRA) ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by T-DM1 monotherapy and neratinib plus capecitabine. For OS, SUCRA ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1 monotherapy, with similar scores. Conclusion: Tucatinib plus trastuzumab with capecitabine, and T-DM1 monotherapy, consistently showed improved PFS and OS versus lapatinib/trastuzumab plus capecitabine and non-targeted treatments.

Lay abstract Although several therapies are used in HER2-positive metastatic breast cancer, direct head-to-head comparisons of these therapies are lacking. We conducted a network meta-analysis, a way of indirectly comparing the results of different clinical trials, to compare how long patients receiving therapy had no disease progression, and also how long patients survived. In terms of avoiding disease progression, tucatinib plus trastuzumab with capecitabine ranked highest, followed by T-DM1 monotherapy and neratinib plus capecitabine. In terms of survival, tucatinib plus trastuzumab with capecitabine ranked highest, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1. Tucatinib in combination with trastuzumab plus capecitabine and also T-DM1 monotherapy consistently demonstrated improved progression-free and overall survival outcomes compared with other therapies.

Preservation of quality of life in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with tucatinib or placebo when added to trastuzumab and capecitabine (HER2CLIMB trial).

AIMS: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB. METHODS: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3-9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit. RESULTS: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm. CONCLUSIONS: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases. CLINICAL TRIAL REGISTRATION: NCT02614794.

Economic burden of central nervous system metastases in human epidermal growth factor receptor 2-positive breast cancer.

Aim: Compare healthcare resource utilization and costs among patients with HER2+ metastatic breast cancer (MBC) with and without central nervous system (CNS) metastases. Methods: Retrospective matched cohort study using IQVIA's PharMetrics® Plus claims database. Results: Patients with CNS metastases (n = 753) experienced more outpatient, emergency room and inpatient visits versus controls (n = 753; all p < 0.05). In the post-index year, median total all-cause healthcare costs were significantly higher among patients with CNS metastases versus controls ($112,402 vs $50,835; p < 0.0001); outpatient costs primarily drove the cost differential. Conclusion: More effective therapies are needed that improve clinical outcomes and reduce economic burden associated with CNS metastases in patients with HER2+ MBC.

Patient-reported outcomes in a phase II, North American study of alectinib in patients with ALK-positive, crizotinib-resistant, non-small cell lung cancer.

BACKGROUND: In a phase II North American study (NP28761; NCT01871805), the anaplastic lymphoma kinase (ALK) inhibitor alectinib demonstrated both systemic and central nervous system (CNS) efficacy with good tolerability in patients with ALK-positive non-small cell lung cancer. We describe patient-reported outcomes (PROs) from the NP28761 study. PATIENTS AND METHODS: PROs and health-related quality of life (HRQoL) benefits were assessed using two self-administered questionnaires (the European Organisation for Research and Treatment of Cancer 30-Item Quality of Life Questionnaire-Core (EORTC QLQ-C30), and the 13-item EORTC QLQ-lung cancer-specific module) at enrolment and every 6 weeks until week 66, disease progression or death. RESULTS: Clinically meaningful mean improvements (≥10 point change from baseline) were observed in 10 domains, including global health status (GHS), role and social functioning, fatigue, pain, dyspnoea, and appetite loss. A clinically meaningful improvement was observed in GHS from the first assessment (6 weeks) until week 60. Alectinib demonstrated a rapid effect, with a median time to symptom improvement, using the composite endpoint of cough, dyspnoea and pain in the chest, of 1.4 months (6.1 weeks) (95% CI 1.4 to 1.6) and a median time to symptom deterioration of 5.1 months (22.1 weeks) (95% CI 2.8 to 6.8). Patients with CNS metastases at baseline experienced comparable HRQoL over the duration of the study as patients without CNS metastases. Exploratory analysis showed that the occurrence of an objective response may be associated with a better HRQoL. CONCLUSIONS: Patients treated with alectinib in this phase II study achieved clinically meaningful improvements in HRQoL and symptoms and had delayed time to symptom deterioration.

Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE).

BACKGROUND: Interleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD). OBJECTIVE: We investigated the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment. METHODS: A randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12. RESULTS: In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate. LIMITATIONS: Protocol-mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations. CONCLUSION: When combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD.

Development and validation of the Ulcerative Colitis patient-reported outcomes signs and symptoms (UC-pro/SS) diary.

BACKGROUND: The clinical course of ulcerative colitis (UC) and the effects of treatment are assessed through patient-reported signs and symptoms (S&S), and endoscopic evidence of inflammation. The Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) measure was developed to standardize the quantification of gastrointestinal S&S of UC in clinical trials through direct report from patient ratings. DESIGN: The UC-PRO/SS was developed by collecting data from concept elicitation (focus groups, and individual interviews), then refined through a process of cognitive interviews of 57 UC patients. Measurement properties, including item-level statistics, scaling structure, reliability, and validity, were evaluated in an observational, four-week study of adults with mild to severe UC (N = 200). RESULTS: Findings from qualitative focus groups and interviews identified nine symptom items covering bowel and abdominal symptoms. The final UC-PRO/SS daily diary includes two scales: Bowel S&S (six items) and Abdominal Symptoms (three items), each scored separately. Each scale showed evidence of adequate reliability (α = 80 and 0.66, respectively); reproducibility (intraclass correlation coefficient = 0.81, 0.71) and validity, including moderate-to-high correlations with the Partial Mayo Score (0.79; 0.45) and Inflammatory Bowel Disease Questionnaire (IBDQ) total score (- 0.70; - 0.61). Scores discriminated by level of disease severity, as defined by the Partial Mayo Score, Patient Global Rating, and Clinician Global Rating (p < 0.0001). CONCLUSIONS: Results suggest that the UC-PRO/SS is a reliable and valid measure of gastrointestinal symptom severity in UC patients. Additional longitudinal data are needed to evaluate the ability of the UC-PRO/SS scores to detect responsiveness and inform the selection of responder definitions.

Development and validation of the Crohn's disease patient-reported outcomes signs and symptoms (CD-PRO/SS) diary.

BACKGROUND: The clinical course of Crohn's disease (CD) and the effect of its treatment are monitored through patient-reported signs and symptoms (S&S), and endoscopic evidence of inflammation. The Crohn's Disease Patient-reported Outcomes Signs and Symptoms (CD-PRO/SS) measure was developed to standardize the quantification of gastrointestinal S&S of CD through direct report from patient ratings. METHODS: The CD-PRO/SS was developed based on data from concept elicitation (focus groups, interviews; n = 29), then refined through cognitive interviews of CD patients (n = 20). Measurement properties, including item-level statistics, scaling structure, reliability, and validity, were examined using secondary analyses of baseline and two-week clinical trial data of adults with moderate-to-severe CD (n = 238). RESULTS: Findings from qualitative interviews identified nine S&S items covering bowel and abdominal symptoms. The final CD-PRO/SS daily diary includes two scales: Bowel S&S (three items) and Abdominal Symptoms (three items), each scored separately. Each scale showed evidence of adequate reliability (α = 0.74 and 0.67, respectively); reproducibility (intraclass correlation coefficient > 0.80), and validity, with the last including moderate correlations with the Inflammatory Bowel Disease Questionnaire bowel symptom score and select items (ranging from r = 0.43-0.54). Scores distinguished patients categorized by patient global ratings of disease severity (p < 0.0001). CONCLUSIONS: Results suggest the CD-PRO/SS is a reliable and valid measure of gastrointestinal symptom severity in CD patients. Additional longitudinal data are needed to evaluate the ability of the CD-PRO/SS scores to detect responsiveness and inform the selection of responder definitions.

Qualitative Development and Content Validity of the Non-small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ), A Patient-reported Outcome Instrument.

PURPOSE: The purpose of this article was to describe the process and results of the preliminary qualitative development of a new symptoms-based patient-reported outcome (PRO) measure intended for assessing treatment benefit in clinical trials of advanced non-small cell lung cancer (NSCLC). METHODS: Individual qualitative interviews were conducted in adults with NSCLC (Stages I-IV) in the United States. Experienced interviewers conducted concept-elicitation (CE) and cognitive interviews using semistructured interview guides. The CE interview guide was used for eliciting spontaneous reports of symptom experiences along with probing to further explore and confirm concepts. Interview transcripts were coded and analyzed by professional qualitative coders, and were summarized by like content using an iterative coding framework. Data from the CE interviews were considered alongside existing literature and clinical expert opinion during an item-generation process, leading to the development of a preliminary version of the NSCLC Symptom Assessment Questionnaire (SAQ). Three waves of cognitive interviews were conducted to evaluate concept relevance, item interpretability, and structure of the draft items and to facilitate further instrument refinement. FINDINGS: Fifty-one subjects (mean [SD] age, 64.9 [11.2] years; 51.0% women) participated in the CE interviews. A total of 1897 expressions of NSCLC-related symptoms were identified and coded in interview transcripts, representing ~42 distinct symptom concepts. A 9-item initial-draft instrument was developed for testing in 3 waves of cognitive interviews with additional subjects with NSCLC (n = 20), during which both paper and electronic versions of the instrument were evaluated and refined. Participant responses and feedback during cognitive interviews led to the removal of 2 items and substantial modifications to others. IMPLICATIONS: The NSCLC-SAQ is a 7-item PRO measure intended for use in advanced NSCLC clinical trials to support medical product labelling. The NSCLC-SAQ uses a 7-day recall period and verbal rating scales. It was developed in accordance with the US Food and Drug Administration's PRO Guidance and scientific best practices, and the resulting qualitative interview data provide evidence of content validity. The NSCLC-SAQ has been prepared in both paper and electronic administration formats and a tablet computer-based version is currently undergoing quantitative testing to confirm its measurement properties and support US Food and Drug Administration qualification.

Qualitative and quantitative validation of the FACIT-fatigue scale in iron deficiency anemia.

BACKGROUND: Fatigue is a burdensome symptom in iron deficiency anemia (IDA). To capture the severity and impact of fatigue appropriately it must be measured using validated scales. This study evaluated the content validity and psychometric validity of the Functional Assessment of Chronic Illness Therapy - fatigue scale (FACIT-fatigue) in IDA patients. METHODS: Qualitative patient interviews were conducted in the United States to evaluate content validity. The psychometric properties of the FACIT-fatigue scale were investigated using data from a phase 3 clinical trial assessing ferumoxytol in patients with a history of unsatisfactory oral iron therapy or in whom oral iron cannot be used. The statistical analysis assessed the acceptability, reliability, validity and responsiveness of the FACIT-fatigue scale. RESULTS: Qualitative interviews showed that fatigue is a central concern to IDA patients and that the FACIT-fatigue scale sufficiently assessed this construct. Psychometric assessment demonstrated that the FACIT-fatigue scale was stable over time (ICC = 0.87) and internally consistent (α = 0.93). The scale demonstrated convergence with other conceptually relevant scales such as SF-36 Vitality (r = 0.74), and distinguished between known groups [i.e., treatment arms (mean difference (95 % CI) = 3.56 (1.68, 5.43), p <0.001) and high vs. low hemoglobin groups (mean difference (95 % CI) = 5.51 (8.59, 2.44) p <0.001)]. Responsiveness was also demonstrated; significant improvements in FACIT-fatigue scale scores corresponded with significant differences between minimal, moderate, and much improved vitality cohorts (p < 0.05). CONCLUSIONS: This research demonstrated that the FACIT-fatigue scale has sound measurement properties and is an appropriate and interpretable assessment of fatigue among IDA patients with various underlying conditions.

Cross-cultural equivalence of the patient- and parent-reported quality of life in short stature youth (QoLISSY) questionnaire.

BACKGROUND: Testing cross-cultural equivalence of patient-reported outcomes requires sufficiently large samples per country, which is difficult to achieve in rare endocrine paediatric conditions. We describe a novel approach to cross-cultural testing of the Quality of Life in Short Stature Youth (QoLISSY) questionnaire in five countries by sequentially taking one country out (TOCO) from the total sample and iteratively comparing the resulting psychometric performance. METHODS: Development of the QoLISSY proceeded from focus group discussions through pilot testing to field testing in 268 short-statured patients and their parents. To explore cross-cultural equivalence, the iterative TOCO technique was used to examine and compare the validity, reliability, and convergence of patient and parent responses on QoLISSY in the field test dataset, and to predict QoLISSY scores from clinical, socio-demographic and psychosocial variables. RESULTS: Validity and reliability indicators were satisfactory for each sample after iteratively omitting one country. Comparisons with the total sample revealed cross-cultural equivalence in internal consistency and construct validity for patients and parents, high inter-rater agreement and a substantial proportion of QoLISSY variance explained by predictors. CONCLUSION: The TOCO technique is a powerful method to overcome problems of country-specific testing of patient-reported outcome instruments. It provides an empirical support to QoLISSY's cross-cultural equivalence and is recommended for future research.

Assessing the quality of life of health-referred children and adolescents with short stature: development and psychometric testing of the QoLISSY instrument.

BACKGROUND: When evaluating the outcomes of treatment in paediatric endocrinology, the health-related quality of life (HrQoL) of the child is to be taken into consideration. Since few self-reported HrQoL instruments exist for children with diagnosed short stature (dSS), the objective of this study was to develop and psychometrically test a targeted HrQoL instrument for use in multinational clinical research. METHODS: The target population were short stature (height<-2 SDS) children and adolescents (age 8-12 and 13-18 years) with a diagnosis of growth hormone deficiency (GHD) or idiopathic short stature (ISS), differing in growth hormone treatment status. Focus group discussions for concept and item generation, piloting of the questionnaire with cognitive debriefing, and instrument field testing with a retest were conducted simultaneously in five countries. After qualitative and preliminary quantitative analyses, psychometric testing of field test data in terms of reliability and validity including confirmatory factor analyses (CFA) was performed. RESULTS: Following item generation from focus group discussions, 124 items were included in a pilot test with a cognitive debriefing exercise providing preliminary feedback on item and domain operating characteristics. A field test with 268 participants showed high internal consistency reliabilities (alpha 0.82-0.95), good correlations with generic measures (up to r=.58), significant known group differences (e.g. in height: F=32, df 244, p<0.001) and an acceptable CFA model fit suggesting construct validity of the three-domain core structure with 22 items, supplemented by three mediator domains with 28 items. CONCLUSIONS: The QoLISSY questionnaire is a promising step forward in assessing the impact of dSS on HrQoL. It is based on items generated from the subjective experience of short stature children referred for endocrine investigation, is validated for use in five languages and it is easy to administer in clinical and research settings.

Parental perception of health-related quality of life in children and adolescents with short stature: literature review and introduction of the parent-reported QoLISSY instrument.

BACKGROUND: Health-related quality of life (HrQoL) of the child diagnosed with short stature is an important outcome to be assessed both from the patient as well as from the parental perspective. The objective of this study was to review the literature on parent-reported HrQoL and to subsequently develop and psychometrically test the parent-reported version of the Quality of Life in Short Stature Youth (QoLISSY) instrument for use in clinical and epidemiologic research. METHODS: A review of the literature on parental assessment of child HrQoL via PUBMED was followed by a psychometric analysis of data collected within the European QoLISSY study, in which 686 eligible parents of short statured children/adolescents (aged 4-18 years) meeting inclusion criteria participated. Patient inclusion criteria were a height below -2 SD, a diagnosis of growth hormone deficiency (GHD) or idiopathic short stature (ISS), and treatment status in terms of receiving or not receiving recombinant human growth hormone therapy. Focus groups eliciting parental HrQoL statements, pilot testing with cognitive debriefing, and a field test in 317 parents with a retest in 148 parents were conducted simultaneously in France, Germany, Spain, Sweden and the UK. The psychometric performance of the parent-reported instrument, developed in parallel to the child/ adolescent self-report version, was assessed using standard tests of reliability and validity. RESULTS: Literature search failed to identify a cross-culturally developed height specific instrument available for both patient self-report and parental observer report. Analysis of the QoLISSY focus group phase conducted separately in children, adolescents and parents yielded 169 items generated from parent focus groups. A cognitive debriefing exercise followed by a pilot test of preliminary psychometric characteristics resulted in deleting poorly performing items. Field testing of the parent-reported version suggested a three-domain core HrQoL structure with 22 items, additional 44 items assessing three mediator domains and two parent specific domains. The parent report version demonstrated good criterion and construct validity as well as internal consistency and test retest reliability. CONCLUSIONS: The QoLISSY parent report questionnaire closes a gap in the simultaneous assessment of parent and child perception of HrQoL in an international context. It is based on items generated from the experience of short statured children, adolescents and their parents and is validated for use in five European languages. It is feasible, relevant for this population, psychometrically sound and is easy to administer in research and clinical settings.