Introduction to special section: quantitative methods.

BackgroundUlcerative colitis (UC) is associated with lower health-related quality of life (HRQoL), and with disease activity predicting lower HRQoL and worse work-related outcomes. The current study examined the burden of UC on patients’ HRQoL, as well as changes in patients’ HRQoL and work-related outcomes following short-term and long-term treatment with multimatrix mesalamine, and their correspondence with changes in disease activity.MethodsData were from an open-label, multinational, prospective trial (ClinicalTrials.gov identifier: NCT01124149) of 717 adults with active mild-to-moderate UC who were treated with 4.8 g/day multimatrix mesalamine tablets once daily for eight weeks (acute phase). Four-hundred sixty-one patients who achieved partial or complete clinical and endoscopic remission subsequently received treatment with daily 2.4 g/day multimatrix mesalamine for 12 months (maintenance phase). At baseline, Week 8, and Month 12, patients were administered patient-reported outcomes (PRO) measures of HRQoL (the SF-12v2® Health Survey [SF-12v2] and Short Inflammatory Bowel Disease Questionnaire) and work-related outcomes (Work Productivity and Activity Impairment questionnaire, UC-specific version). SF-12v2 scores were compared to the U.S. general population using Analysis of Variance models to assess burden of UC on HRQoL. Mixed-effects repeated-measures models compared PRO scores across visits to assess change in PRO scores over time. Correlations examined the correspondence of changes in PRO scores with changes on a modified UC disease activity index (UC-DAI).ResultsBaseline burden of disease observed on all SF-12v2 domains was partially eliminated at Week 8 and completely eliminated at Month 12. Statistically significant improvements from baseline were observed at both Week 8 and Month 12 for all PRO scores (all P < 0.001). Decreases in UC-DAI scores significantly predicted improvements in PRO scores during the acute treatment phase.ConclusionsPatients with UC receiving daily multimatrix mesalamine treatment showed significant improvements in all measured domains of HRQoL and work-related outcomes. Patients who achieved partial or complete clinical and endoscopic remission maintained these improvements for most of these domains over 12 months with continued daily treatment. Changes in HRQoL and work-related outcomes were inversely related to changes in disease activity. Findings support the effectiveness of multimatrix mesalamine for improving, and sustaining improvements, in HRQoL and work-related outcomes.

Although the incidence of ovarian cancer is less than that of other female cancers, the morbidity and mortality associated with the disease course is high. Because treatment involves radical surgery and intense courses of chemotherapy, health-related quality of life (HRQOL) is often compromised. Most patients recur post-first-line therapy and undergo multiple rounds of chemotherapy. Thus, HRQOL is further disrupted. As the ongoing search for optimal therapies in both the first-line and recurrent setting continues, much attention is paid towards clinical trial design and implementation. Over the last decade, patient-reported outcomes and HRQOL measurement have become an integral part of these trials. HRQOL data are valued in examining the extent of treatment benefit and therefore can aid in decision-making during active treatment and palliative care. HRQOL and patient-reported outcome measurement is also useful in determining symptom prevalence, severity and management. This article highlights the state of the science of HRQOL measurement in clinical trial design and outcomes. In addition, symptom management in ovarian cancer and its ability to modulate quality of life will be explored.

Impact of preoperative weakness and duration of symptoms on health-related quality-of-life outcomes following anterior cervical discectomy and fusion

ABSTRACTBackground: The analgesic effect of long-acting opioids, such as transdermal fentanyl, has been demonstrated in patients with cancer, neuropathic pain and chronic low back pain (CLBP). However, the broader effect of long-acting opioids on the patient's health-related quality of life (HRQoL) is less well known.Objective: To evaluate HRQoL outcomes in CLBP patients treated with transdermal fentanyl.Research design and methods: An observational study was conducted at 17 clinical centers in the US. Eligible patients had CLBP diagnosis for at least 3 months and were taking short-acting opioids chronically, and then initiated transdermal fentanyl treatment. Patients completed the Treatment Outcomes in Pain Survey (TOPS), which includes the SF‐36 Health Survey, at baseline and ≥ 9 weeks of treatment. The HRQoL burden of CLBP was determined by comparing CLBP patients’ SF‐36 scores to the general US population and low back pain patient norms. HRQoL outcomes were determined by comparing baseline and follow-up TOPS and SF‐36 scores. Additionally, HRQoL outcomes were evaluated across patient groups stratified by changes in pain intensity ratings as measured by an 11-point numerical rating scale.Results: At baseline CLBP patients (N = 131) scored one-to-two standard deviations (SD) below age and gender adjusted SF‐36 general population norms (MANOVA F = 127.1, p < 0.0001) and significantly lower than low back pain norms (MANOVA F = 125.3, p < 0.0001). At follow-up, significant improvement ( p < 0.05) was observed on six of the SF‐36 scales and both SF‐36 summary measures and five of the six TOPS pain-related scales. The magnitude of change in scores in effect size units among these scales ranged from 0.17 to 0.80, which are considered small to large effect size changes. HRQoL score improvement was greatest among patients experiencing the greatest pain relief.Conclusion: CLBP patients who chronically used short-acting opioids showed tremendous HRQoL burden. Favorable HRQoL outcomes were observed among patients who reported pain relief.

OBJECTIVE The emphasis on health-related quality of life (HRQOL) outcomes is increasing, along with an emphasis on evidence-based medicine. However, there is a notable paucity of validated HRQOL instruments for the pediatric population. Furthermore, no standardization or consensus currently exists concerning which HRQOL outcome measures ought to be used in pediatric neurosurgery. The authors wished to identify HRQOL outcomes used in pediatric neurosurgery research over the past 10 years, their frequency, and usage trends. METHODS Three top pediatric neurosurgical journals were reviewed for the decade from 2005 to 2014 for clinical studies of pediatric neurosurgical procedures that report HRQOL outcomes. Similar studies in the peer-reviewed journal Pediatrics were also used as a benchmark. Publication year, level of evidence, and HRQOL outcomes were collected for each article. RESULTS A total of 31 HRQOL studies were published in the pediatric neurosurgical literature over the study period. By comparison, there were 55 such articles in Pediatrics. The number of publications using HRQOL instruments showed a significant positive trend over time for Pediatrics (B = 0.62, p = 0.02) but did not increase significantly over time for the 3 neurosurgical journals (B = 0.12, p = 0.5). The authors identified a total of 46 different HRQOL instruments used across all journals. Within the neurosurgical journals, the Hydrocephalus Outcome Questionnaire (HOQ) (24%) was the most frequently used, followed by the Health Utilities Index (HUI) (16%), the Pediatric Quality of Life Inventory (PedsQL) (12%), and the 36-Item Short Form Health Survey (SF-36) (12%). Of the 55 articles identified in Pediatrics, 22 (40%) used a version of the PedsQL. No neurosurgical study reached above Level 4 on the Oxford Centre for Evidence-Based Medicine (OCEBM) system. However, multiple studies from Pediatrics achieved OCEBM Level 3, several were categorized as Level 2, and one reached Level 1. CONCLUSIONS The frequency of studies using HRQOL outcomes in pediatric neurosurgical research has not increased over the past 10 years. Within pediatric neurosurgery, high-quality studies and standardization are lacking, as compared with contemporary studies in Pediatrics. In general, although the HOQ, HUI, PedsQL, and SF-36 instruments are emerging as standards in pediatric neurosurgery, even greater standardization across the specialty is needed, along with the design and implementation of more rigorous studies.

Health-related quality of life (HRQoL) measures are increasingly used in trials as primary outcome measures. Investigators are now asking statisticians for advice on how to plan and analyse studies using such outcomes. HRQoL outcomes, like the SF-36, are usual measured on an ordinal scale, although most investigators assume that there exists an underlying continuous latent variable and that the actual measured outcomes (the ordered categories) reflect contiguous intervals along this continuum. The ordinal scaling of HRQoL measures means they tend to generate data that have discrete, bounded and skewed distributions. Thus, standard methods of analysis that assume Normality and constant variance may not be appropriate. For this reason, conventional statistical advice would suggest non-parametric methods be used to analyse HRQoL data. The bootstrap is one such computer intensive non-parametric method for estimating sample sizes and analysing data. We describe three methods of estimating sample sizes for two-group cross-sectional comparisons of HRQoL outcomes. We then compared the power of the three methods for a two-group cross-sectional study design using bootstrap simulation. The results showed that under the location shift alternative hypothesis, conventional methods of sample size estimation performed well, particularly Whitehead's method. Whitehead's method is recommended if the HRQoL outcome has a limited number of discrete values (<7) and/or the expected proportion of cases at either of the bounds is high. If a pilot data set is readily available then bootstrap simulation will provide a more accurate and reliable estimate, than conventional methods.Finally, we used the bootstrap for hypothesis testing and the estimation of standard errors and confidence intervals for parameters, in an example data set. We then compared and contrasted the bootstrap with standard methods of analysing HRQoL outcomes. In the data set studied, with the SF-36 outcome, the use of the bootstrap for estimating sample sizes and analysing HRQoL data produces results similar to conventional statistical methods. These results suggest that bootstrap methods are not more appropriate for analysing HRQoL outcome data than standard methods.

Health-related quality of life has become an important outcome in cancer treatment. Detailed health-related quality of life measures were taken as part of a trial of follow-up of patients with colon cancer by general practitioners and surgeons. This study was designed as a longitudinal assessment of health-related quality of life after treatment for carcinoma of the colon and patient satisfaction with two different settings of follow-up (general practitioners vs. surgeons). A total of 338 patients were recruited into randomized (n = 203) and patient preference (n = 135) follow-up groups. Prospectively assessed physical and mental health-related quality of life measures and patient satisfaction are reported during two years. Elderly and less educated patients prefer follow-up by general practitioners over surgeons. Overall, physical health-related quality of life is reduced early after treatment; however, this returns to normal levels at one year. Mental quality of life, anxiety, and depression are at or above population levels throughout the two-year follow-up period. There were no differences in physical or psychologic health-related quality of life measures between general practitioner and surgeon groups at any time during follow-up. Overall, more advanced Dukes stage is associated with a trend to improved mental health-related quality of life. Patients' ability to choose the setting of follow-up has no influence on health-related quality of life compared with random allocation to general practitioner or surgeon. Patients are equally highly satisfied with follow-up by general practitioner or surgeon. After recovery from treatment for colon cancer, health-related quality of life is similar to the general population. Good health-related quality of life outcomes and high patient satisfaction are as well provided by general practitioners in the community setting as by surgeon review.

Extensive Variability in Platelet Count, Bleeding, and Quality of Life Outcome Measures in Adult and Pediatric Immune Thrombocytopenia: An Appraisal from a Critical Review of the Literature

We describe and compare four different methods for estimating sample size and power, when the primary outcome of the study is a Health Related Quality of Life (HRQoL) measure. These methods are: 1. assuming a Normal distribution and comparing two means; 2. using a non-parametric method; 3. Whitehead's method based on the proportional odds model; 4. the bootstrap. We illustrate the various methods, using data from the SF-36. For simplicity this paper deals with studies designed to compare the effectiveness (or superiority) of a new treatment compared to a standard treatment at a single point in time. The results show that if the HRQoL outcome has a limited number of discrete values (< 7) and/or the expected proportion of cases at the boundaries is high (scoring 0 or 100), then we would recommend using Whitehead's method (Method 3). Alternatively, if the HRQoL outcome has a large number of distinct values and the proportion at the boundaries is low, then we would recommend using Method 1. If a pilot or historical dataset is readily available (to estimate the shape of the distribution) then bootstrap simulation (Method 4) based on this data will provide a more accurate and reliable sample size estimate than conventional methods (Methods 1, 2, or 3). In the absence of a reliable pilot set, bootstrapping is not appropriate and conventional methods of sample size estimation or simulation will need to be used. Fortunately, with the increasing use of HRQoL outcomes in research, historical datasets are becoming more readily available. Strictly speaking, our results and conclusions only apply to the SF-36 outcome measure. Further empirical work is required to see whether these results hold true for other HRQoL outcomes. However, the SF-36 has many features in common with other HRQoL outcomes: multi-dimensional, ordinal or discrete response categories with upper and lower bounds, and skewed distributions, so therefore, we believe these results and conclusions using the SF-36 will be appropriate for other HRQoL measures.

Thalassemia is a disorder of hemoglobin (Hb) synthesis characterized by chronic hemolysis. In β-thalassemias major (β-TM), patients require regular transfusion at an early age due to severe anemia. Subsequently, intensive chelation therapy is initiated to mitigate the effects of the resultant iron overload. Clinical disease burden and the demanding treatment can affect health-related quality of life (HRQoL) outcomes in this population. The aim of this study was to assess HRQoL outcomes in Egyptian pediatric thalassemia patients. Patients were enrolled simultaneously from the hematology clinic at the National Research Institute in Cairo, Egypt. The Arabic version of SF36 tool was used to assess HRQoL outcomes. Socioeconomic data were collected by patient and parent interviews. Clinical data were collected by review of medical records. One hundred and thirty patients and 60 controls were enrolled, with a mean age of 5.4 ± 3.2 years and 6.3 ± 3.0, respectively. The HRQoL outcome scores were lower in all domains in the thalassemia group compared to the control group (p = 0.0001). Transfusion-dependent (TD) patients had lower HRQoL scores compared to nontransfusion-dependent (NTD) patients (p = 0.0001). Patient education and maternal education were independently associated with better HRQoL scores (p = 0.007, p = 0.028, respectively). Residents of rural areas reported lower scores compared to urban residents (p = 0.026). Thalassemia was associated with lower HRQoL scores, in all domains, compared to HRQoL in unaffected controls. Chronic transfusion independence, patient education, and maternal education were all associated with higher HRQoL scores. Psychological, social, and economic support for families with thalassemia are all essential tools to improve HRQoL outcomes.

138. Radiographic malalignment has a far greater impact on clinical outcomes than perioperative and postoperative complications in ASD surgery

There is debate about the value of measuring health-related quality of life (HRQL) in clinical trials in oncology because of evidence suggesting that HRQL does not influence clinical decisions. Analysis of HRQL in surgical trials, however, may inform decision making because it provides detailed assessment of the immediate detrimental short-term impact of surgery on HRQL that needs to be considered against the long-term survival benefits and functional outcomes of surgery. This study evaluated whether HRQL in randomized trials in surgical oncology contributes to clinical decision making. A systematic review identified randomized trials in surgical oncology with HRQL. Trials were evaluated independently by two reviewers and the value of HRQL in clinical decision making was categorized in three ways: whether trial investigators reported that HRQL influenced final treatment recommendations, whether trial investigators reported that HRQL would be useful for informed consent, and whether HRQL was assessed robustly according to predefined criteria. Thirty-three randomized trials with valid HRQL questionnaires were identified; 22 (67%) concluded that HRQL outcomes influenced treatment decisions or provided valuable data for informed consent, and seven of these trials had robust HRQL design. Another five trials had robust HRQL design but investigators reported that HRQL outcomes were not clinically important enough to influence treatment recommendations. In surgical trials in oncology, HRQL informed clinical decision making. It is recommended that HRQL be included in relevant surgical trials, and that information be used to inform clinicians and patients about the impact of surgery on short- and long-term HRQL.

Positive affect is associated with resiliency and beneficial health outcomes, but little is known about associations between positive affect and health-related quality of life (HRQOL) in Huntington's disease (HD). This longitudinal study determined the association between positive affect and several HRQOL outcomes in persons with HD. Functional status was examined as a moderator of the association between positive affect and HRQOL. Participants, with premanifest (i.e., genetically at risk but no clinical diagnosis, n = 50) and manifest HD (early-stage n = 171; late-stage n = 101), completed a measure of positive affect and well-being and several HRQOL measures at baseline, 12-, and 24-month follow-ups. UHDRS Functional Assessment scale indicated functional status. Positive affect was associated with better HRQOL for persons with premanifest and manifest HD over the 24-month time frame. These associations were moderated by functional status. For persons with higher functional status, positive affect was associated with better HRQOL, including less depression, lower anxiety, less anger, better social role satisfaction, better executive functions, greater upper extremity function, less dyscontrol, and less concern with death and dying. For persons with lower functional status, positive affect was not associated with HRQOL. Positive affect predicted better self-reported HRQOL over a 24-month period in persons with premanifest and manifest HD, particularly when participnats had better functional status. Interventions to enhance positive affect in HD may have beneficial effects on HRQOL.

245 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care, with increasing data demonstrating improved survival outcomes using ICIs among patients with advanced gastroesophageal cancer (aGEC). ICIs are also associated with a lower incidence of grade ≥3 adverse effects (AEs) compared to chemotherapy (CT), suggesting that ICIs may have favorable effects on health-related quality of life (HRQoL). This meta-analysis sought to evaluate the effects of ICIs on the HRQoL of patients with aGEC. Methods: An online bibliographic search was conducted on Medline via PubMed using MeSH-based terms to retrieve randomized controlled trials (RCTs) that evaluated the effects of ICIs on HRQoL in patients with aGEC. We included RCTs that incorporated ICIs as part of the intervention arm either as monotherapy (second-line) or as a combination therapy (first-line) with another ICI or CT. We combined the HRQoL measures into a meta-analysis using standard random effects models, from which estimates of the average mean difference (MD) were obtained with 95% confidence intervals. We assessed heterogeneity of the study outcomes using the Q and I2 statistics. Results: 11 phase-3 RCTs were included, with a mean enrollment of 820 patients. Most (n=X) of the RCTs had ICI plus CT combination in the intervention arm, three had ICIs as monotherapy, and one had doublet ICI therapy in the intervention arm. All RCTs had CT for the control arm. Collectively, trials reported 37 HRQoL measures using 5 different HRQoL tools. The pooled analysis favored the intervention over the control arm in terms of Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scores [MD 2.7 (95% CI 0.1 to 5.3), p&lt;0.05]. In a subgroup analysis of 8 RCTs comparing combination therapy with ICIs plus CT versus CT alone, the effect estimates favored the ICI arm regarding the FACT-E [MD 2.7 (95% CI 0.1 to 5.3), p&lt;0.05] and the EORTC QLQ-OES18 pain scale [MD -2.2 (95% CI -4.3 to -0.2), p&lt;0.05]. We found no statistically significant differences in HRQoL scales in subgroup analysis of ICI monotherapy versus CT. Conclusions: In this meta-analysis, we found that the inclusion of ICIs as first-line treatment for aGECs yielded better HRQoL outcomes than CT. Further research on the impact of ICIs on HRQoL is needed, yet with increasing evidence that ICIs improve survival outcomes in patients with aGEC, these corresponding benefits with HRQoL are encouraging.[Table: see text]

The aims of this focused review of the literature on children surviving critical illness were to (1) determine whether health-related quality of life (HRQL) represents a clinically meaningful outcome measure for children surviving critical illness and (2) evaluate the HRQL measures implemented in pediatric critical care studies to date. This was a focused review of the literature from 1980 to 2015 based on a search of EMBASE/PubMed, MEDLINE and PsycInfo assessing trends and determinants of HRQL outcomes in children surviving critical illness. We also evaluated the psychometric properties of the HRQL instruments used in the studies identified by examining each measure's reported reliability, validity and sensitivity to clinical change. The literature search identified 253 pediatric articles for potential inclusion in the review, among which data from 78 studies were ultimately selected for inclusion. Of the 22 measures utilized in the studies reviewed, only four demonstrated excellent psychometric properties for use in pediatric critical care trials. Trends in HRQL identified in the studies reviewed suggest significant ongoing morbidity for children surviving critical illness. Key determinants of poor HRQL outcomes include reason for PICU admission (sepsis, meningoencephalitis, trauma), antecedents (chronic comorbid conditions), treatments received (prolonged cardiopulmonary resuscitation, long-stay patients, invasive technology), psychological outcomes (post-traumatic stress disorder, parent anxiety/depression) and social and environmental characteristics (low socioeconomic status, parental education and functioning). Validated pediatric HRQL instruments are now available. Significant impact on HRQL has been demonstrated in acute and acute on chronic critical illness. Future pediatric critical care interventional trials should include both mortality as well as long-term HRQL measurements to truly ascertain the full impact of critical illness in children.