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1.  Predictors of Significant Worsening of Patient-Reported Fatigue over a One-Month Timeframe in Ambulatory Patients with Common Solid Tumors 
Cancer  2013;120(3):442-450.
Understanding the determinants of fatigue worsening may help distinguish between different fatigue phenotypes and inform clinical trial designs.
Patients and Methods
Patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled from multiple sites. At enrollment during an outpatient visit and 4–5 weeks later patients rated their symptoms on a 0–10 numerical rating scale. A 2-point change was considered clinically significant for fatigue change. Effects of demographic and clinical factors on patient-reported fatigue were examined using logistic regression models.
3123 patients were enrolled at baseline and 3032 were analyzable for fatigue change. At baseline, 23% had no fatigue, 35% mild, 25% moderate, and 17% severe. Key parameters in our model of fatigue worsening includes fatigue at baseline (OR 0.75), disease status (OR 1.99), performance status (OR 1.38), history of depression (OR 1.28), patient perception of bother due to comorbidity (OR 1.26) and treatment exposures including recent cancer treatment (OR 1.77), and use of corticosteroids (1.37). The impact of gender was examined only in colorectal and lung cancer patients, and it was a significant factor with men most likely to experience worsening of fatigue (OR=1.46).
Predictors of fatigue worsening include multiple factors that are difficult to modify: baseline fatigue level, gender, disease status, performance status, recent cancer treatment, bother due to comorbidity, and history of depression. Future fatigue prevention and treatment trial designs should account for key predictors of worsening fatigue.
PMCID: PMC4134680  PMID: 24151111
cancer fatigue; symptom management; medical oncology; ambulatory care
2.  A Literature Synthesis of Symptom Prevalence and Severity in Persons Receiving Active Cancer Treatment 
Patients with cancer experience acute and chronic symptoms caused by their underlying disease or by the treatment. While numerous studies have examined the impact of various treatments on symptoms experienced by cancer patients, there are inconsistencies regarding the symptoms measured and reported in treatment trials. This article presents a systematic review of the research literature of the prevalence and severity of symptoms in patients undergoing cancer treatment.
A systematic search for studies of persons receiving active cancer treatment was performed with the search terms of “multiple symptoms” and “cancer” for studies involving patients over the age of 18 years and published in English during the years 2001 to 2011. Search outputs were reviewed independently by seven authors, resulting in the synthesis of 21 studies meeting criteria for generation of an Evidence Table reporting symptom prevalence and severity ratings.
Data were extracted from 21 multi-national studies to develop a pooled sample of 4067 cancer patients in whom the prevalence and severity of individual symptoms was reported. In total, the pooled sample across the 21 studies was comprised of 62% female, with a mean age of 58 years (range: 18 to 97 years). A majority (62%) of these studies assessed symptoms in homogeneous samples with respect to tumor site (predominantly breast and lung cancer), while 38% of the included studies utilized samples with mixed diagnoses and treatment regimens. Eighteen instruments and structured interviews were including those measuring single symptoms, multi-symptom inventories, and single symptom items drawn from HRQOL or health status measures. The MD Anderson Symptom Inventory (MDASI) was the most commonly used instrument in the studies analyzed (n=9 studies; 43%), while the Functional Assessment of Cancer Therapy (FACT-G), Hospital Anxiety and Depression Subscale (HADS-D), Medical Outcomes Survey Short Form-36 (SF-36), and Symptom Distress Scale (SDS) were each employed in two studies. Forty-seven symptoms were identified across the 21 studies which were then categorized into 17 logical groupings. Symptom prevalence and severity were calculated across the entire cohort and also based upon sample sizes in which the symptoms were measured providing the ability to rank symptoms.
Symptoms are prevalent and severe among patients with cancer. Therefore, any clinical study seeking to evaluate the impact of treatment on patients should consider including measurement of symptoms. This study demonstrates that a discrete set of symptoms is common across cancer types. This set may serve as the basis for defining a “core” set of symptoms to be recommended for elicitation across cancer clinical trials, particularly among patients with advanced disease.
PMCID: PMC4299699  PMID: 23314601
Cancer; symptoms; systematic review
3.  Establishing a Common Metric for Self-Reported Anxiety: Linking the MASQ, PANAS, and GAD-7 to PROMIS Anxiety 
Journal of anxiety disorders  2013;28(1):88-96.
Researchers and clinicians wishing to assess anxiety must choose from among numerous assessment options, many of which purport to measure the same or a similar construct. A common reporting metric would have great value, and can be achieved when similar instruments are administered to a single sample and then linked to each other to produce cross-walk score tables. Using item response theory (IRT), we produced cross-walk tables linking three popular “legacy” anxiety instruments – MASQ (N = 743), GAD-7 (N = 748), and PANAS (N = 1120) – to the anxiety metric of the NIH Patient Reported Outcomes Measurement Information System (PROMIS®). The linking relationships were evaluated by resampling small subsets and estimating confidence intervals for the differences between the observed and linked PROMIS scores. Our results allow clinical researchers to retrofit existing data of three commonly-used anxiety measures to the PROMIS Anxiety metric and to compare clinical cut-off scores.
PMCID: PMC4046852  PMID: 24508596
anxiety; linking; PROMIS; MASQ; GAD-7; PANAS
4.  Intracerebral Hemorrhage and Delirium Symptoms. Length of Stay, Function, and Quality of Life in a 114-Patient Cohort 
Rationale: The prognostic significance of delirium symptoms in intensive care unit (ICU) patients with focal neurologic injury is unclear.
Objectives: To determine the relationship between delirium symptoms and subsequent functional outcomes and quality of life (QOL) after intracerebral hemorrhage.
Methods: We prospectively enrolled 114 patients. Delirium symptoms were routinely assessed twice daily using the Confusion Assessment Method for the ICU by trained nurses. Functional outcomes were recorded with modified Rankin Scale (scored from 0 [no symptoms] to 6 [dead]), and QOL outcomes with Neuro-QOL at 28 days, 3 months, and 12 months.
Measurements and Main Results: Thirty-one (27%) patients had delirium symptoms (“ever delirious”), 67 (59%) were never delirious, and the remainder (14%) had persistent coma. Delirium symptoms were nearly always hypoactive, were detected mean 6 days after intracerebral hemorrhage presentation, and were associated with longer ICU length of stay (mean 3.5 d longer in ever vs. never delirious patients; 95% confidence interval, 1.5–8.3; P = 0.004) after correction for age, admit National Institutes of Health (NIH) Stroke Scale, and any benzodiazepine exposure. Delirium symptoms were associated with increased odds of poor outcome at 28 days (odds ratio, 8.7; 95% confidence interval, 1.4–52.5; P = 0.018) after correction for admission NIH Stroke Scale and age, and with worse QOL in the domains of applied cognition–executive function and fatigue after correcting for the NIH Stroke Scale, age, benzodiazepine exposure, and time of follow-up.
Conclusions: After focal neurologic injury, delirium symptoms were common despite low rates of infection and sedation exposure, and were predictive of subsequent worse functional outcomes and lower QOL.
PMCID: PMC3919076  PMID: 24102675
delirium; outcomes; quality of life
5.  Characterizing fatigue associated with sunitinib and its impact on health-related quality of life in patients with metastatic renal cell carcinoma 
Cancer  2014;120(12):1871-1880.
Using phase 3 trial data for sunitinib versus interferon (IFN)-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life (HRQoL).
Patients received sunitinib at a dose of 50 mg/day on a schedule of 4 weeks on/2 weeks off (375 patients) or IFN-α at a dose of 9 MU subcutaneously 3 times per week (360 patients). HRQoL was self-assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index–15-item (FKSI-15) questionnaire, with fatigue assessed using its Disease-Related Symptoms subscale. Fatigue was also assessed by providers using Common Terminology Criteria for Adverse Events (CTCAE). A repeated-measures model (M1) and random intercept-slope model (M2) characterized sunitinib-associated fatigue over time. Another repeated-measures model examined the relationship between HRQoL scores and CTCAE fatigue grade.
M1 demonstrated that the initial increase in patient-reported fatigue with sunitinib was worst during cycle 1, with mean values numerically better at subsequent cycles; most pairwise comparisons of consecutive CTCAE fatigue cycle means were not found to be statistically significant. M2 demonstrated that the overall trend (slope) for patient-reported and CTCAE fatigue with sunitinib was not statistically different from 0. The relationship between most HRQoL scores and CTCAE fatigue was close to linear regardless of treatment, with lower scores (worse HRQoL) corresponding to higher fatigue grade. The majority of HRQoL scores were better with sunitinib versus IFN-α for the same CTCAE fatigue grade.
Patients reported worse fatigue during the first sunitinib cycle. However, in subsequent consecutive cycles, less fatigue was reported with no statistically significant worsening. CTCAE fatigue assessment may not fully capture patient treatment experience. Cancer 2014;120:1871–1880. © 2014 American Cancer Society.
Using phase 3 trial data for sunitinib versus interferon-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life. Patients reported worse fatigue during the first sunitinib cycle, but in subsequent consecutive cycles less fatigue was reported with no statistically significant worsening; provider-assessed fatigue did not appear to fully capture patient treatment experience.
PMCID: PMC4231253  PMID: 24634003
sunitinib; metastatic renal cell carcinoma; fatigue; health-related quality of life; phase 3
6.  Development and validation of the positive affect and well-being scale for the neurology quality of life (Neuro-QOL) measurement system 
To develop and validate an item-response theory-based patient-reported outcomes assessment tool of positive affect and well-being (PAW). This is part of a larger NINDS-funded study to develop a health-related quality of life measurement system across major neurological disorders, called Neuro-QOL.
Informed by a literature review and qualitative input from clinicians and patients, item pools were created to assess PAW concepts. Items were administered to a general population sample (N = 513) and a group of individuals with a variety of neurologic conditions (N = 581) for calibration and validation purposes, respectively.
A 23-item calibrated bank and a 9-item short form of PAW was developed, reflecting components of positive affect, life satisfaction, or an overall sense of purpose and meaning. The Neuro-QOL PAW measure demonstrated sufficient unidimensionality and displayed good internal consistency, test–retest reliability, model fit, convergent and discriminant validity, and responsiveness.
The Neuro-QOL PAW measure was designed to aid clinicians and researchers to better evaluate and understand the potential role of positive health processes for individuals with chronic neurological conditions. Further psychometric testing within and between neurological conditions, as well as testing in non-neurologic chronic diseases, will help evaluate the generalizability of this new tool.
PMCID: PMC3855608  PMID: 23526093
Positive affect; Psychological well-being; Quality of life; Measurement; Patient-reported outcomes; Neurological conditions
7.  Recommendations for High-Priority Research on Cancer-Related Fatigue in Children and Adults 
Over the past decades, some scientific progress has been made in understanding and treating cancer-related fatigue (CRF). However, three major problems have limited further progress: lack of agreement about measurement, inadequate understanding of the underlying biology, and problems in the conduct of clinical trials for CRF. This commentary reports the recommendations of a National Cancer Institute Clinical Trials Planning Meeting and an ongoing National Cancer Institute working group to address these problems so that high-priority research and clinical trials can be conducted to advance the science of CRF and its treatment. Recommendations to address measurement issues included revising the current case definition to reflect more rigorous criteria, adopting the Patient Reported Outcomes Measurement Information System fatigue scales as standard measures of CRF, and linking legacy measures to the scales. With regard to the biology of CRF, the group identified the need for longitudinal research to examine biobehavioral mechanisms underlying CRF and testing mechanistic hypotheses within the context of intervention research. To address clinical trial issues, recommendations included using only placebo-controlled trial designs. setting eligibility to minimize sample heterogeneity or enable subgroup analysis, establishing a CRF severity threshold for participation in clinical trials, conducting dissemination trials of efficacious interventions (such as exercise), and combining nonpharmacologic and pharmacologic interventions to exploit the potential synergy between these approaches. Accomplishing these goals has the potential to advance the science of CRF and improve the clinical management of this troubling symptom.
PMCID: PMC3888121  PMID: 24047960
8.  Fatigue in patients with advanced renal cell carcinoma receiving sunitinib on an intermittent versus continuous dosing schedule in a randomized phase II trial 
Cancer Medicine  2014;3(5):1353-1358.
A phase II trial in advanced renal cell carcinoma (RCC) found no benefit in efficacy or safety between patients receiving oral sunitinib 50 mg/day for 4 weeks followed by 2-week off-treatment (Schedule 4/2) and those receiving 37.5 mg continuous daily sunitinib. We hypothesized that fatigue would have a more variable “on-off” effect with the 4/2 schedule. A total of 292 patients completed two fatigue-related items on Days 1 and 29 of each treatment cycle. Mean absolute slopes were compared across treatments. A planned analysis of item “I feel fatigued” demonstrated that the mean absolute slope was greater in Schedule 4/2 compared to continuous dosing (0.042 vs. 0.032, P = 0.003), and analysis based on the change from Day 1 to Day 29 (0.52 vs. 0.21, P = 0.002) and, separately, Day 29 to the next Day 1 (−0.38 vs. −0.05, P < 0.001) showed the changes to be significantly larger in Schedule 4/2 than continuous dosing. “I have a lack of energy” showed a similar pattern graphically, however, the planned analysis was not statistically significant based on the absolute slopes but was when Day 1 to Day 29 and Day 29 to Day 1 changes were analyzed separately. The 4/2 arm was associated with a greater degree of variability in fatigue reflecting a possible “on-off” effect whereby patients receiving the 4/2 schedule reported less fatigue at the beginning of each cycle compared to Day 29. The findings can inform care for individuals with advanced RCC receiving intermittent dosing of sunitinib.
PMCID: PMC4302685  PMID: 25044922
Fatigue; quality of life; renal cell carcinoma; sunitinib
9.  New English and Spanish Social Health Measures Will Facilitate Evaluating Health Determinants 
To develop psychometrically sound, culturally relevant and linguistically equivalent English and Spanish self-report measures of social health guided by a comprehensive conceptual model and applicable across chronic illnesses.
The Patient-Reported Outcomes Measurement Information System (PROMIS) Social Health Workgroup implemented a mixed methods approach to evaluate earlier results (v1.0); expand and refine domain definitions and items; translate items into Spanish; and obtain qualitative feedback. Computer-based and paper/pencil questionnaire administration was conducted with a variety of U.S. respondent samples during 2009–2012. Analyses included exploratory factor analysis (EFA), confirmatory factor analysis (CFA), two-parameter logistic item response theory (IRT) modeling, evaluation of differential item functioning (DIF), and evaluation of criterion and construct validity.
Qualitative feedback supported the conceptualization of the Social Health domain framework (Social Function and Social Relationships sub-components). Validation testing participants (n=2,208 English; n=644 Spanish) were diverse in terms of gender, age, education and ethnicity/race. EFA, CFA and IRT identified seven unidimensional factors with good model fit. There was no DIF by language, and good evidence of criterion and construct validity.
PROMIS English and Spanish language instruments (v2.0), including computer-adaptive tests and fixed-length short forms, are publicly available for assessment of Social Function (Ability to Participate in Social Roles and Activities, and Satisfaction with Social Roles and Activities) and Social Relationships (Companionship; Emotional, Informational and Instrumental Support; and Social Isolation). Measures of social health will play a key role in applications that use ecologic (or determinants of health) models that emphasize how patients’ social environments influence their health.
PMCID: PMC4159098  PMID: 24447188
patient-reported outcomes; social health; social function; social relationships; Hispanic Americans; psychometrics
10.  The Stigma Scale for Chronic Illnesses 8-item version (SSCI-8): Development, validation, and use across neurological conditions 
Although the impact of stigma has been highlighted for epileptic populations, the experiences of people living with other neurological conditions have been less studied. In order to promote research on stigma among people with neurological conditions, we sought to develop and psychometrically validate an 8-item questionnaire measuring internalised and enacted stigma experienced by people with epilepsy, multiple sclerosis (MS), Parkinson’s disease (PD), stroke, and amyotrophic lateral sclerosis (ALS).
We used Item Response Theory (IRT) methodologies to select items and field-tested our items with 587 participants from 8 academic medical centres across the United States.
We conducted Exploratory and Confirmatory Factor Analysis as well as examined scale the reliability and validity. In addition, we conducted an analysis of variance (ANOVA) test to examine mean total score differences across the 5 neurological conditions. Data from people across conditions revealed that the shortened instrument conformed to an essentially unidimensional model of multi-faceted stigma as a 1-factor questionnaire with correlated residuals on a pair of items that distinctly measured internalised stigma.
Preliminary evidence suggests that the Stigma Scale for Chronic Illness 8-item version (SSCI-8) fits a unidimensional model, which assesses enacted and internalised stigma, and has adequate internal consistency/reliability and validity in relation to psychological distress and patient performance. Our results suggest fairly low stigma for neurological populations. In addition, our results suggest that stigma may be more severe for patients with ALS relative to those with MS and PD. Our results suggest that the scale could be used practically in the clinic setting to examine stigma without the patient burden associated with lengthier scales.
PMCID: PMC3758464  PMID: 22639392
neurological disorder; epilepsy; quality of life; stigma; measurement
11.  Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort 
Cancer  2013;119(13):2375-2382.
More than 80,000 postmenopausal breast cancer patients in the US each year are estimated to begin a five-year course of aromatase inhibitors (AIs) to prevent recurrence. AI-related arthralgia (joint pain and/or stiffness) may contribute to nonadherence, but longitudinal data are needed on arthralgia risk factors, trajectories, and background in postmenopause.
To describe one-year arthralgia trajectories and baseline covariates among AI patients and a postmenopausal comparison group.
Patients initiating AIs (n=91) were surveyed at the time of AI initiation and at six repeated assessments over one year. A comparison group of postmenopausal women without breast cancer (n=177) completed concomitantly-timed surveys. Numeric rating scales (0–10) were used to measure pain in eight joint pair groups (bilateral fingers, wrists, elbows, shoulders, hips, knees, ankles, and toes). Poisson regression models were used to analyze arthralgia trajectories and risk factors.
By week six, the AI-initiating group had more severe arthralgia than did the comparison group (ratio of means=1.8, (95% CI 1.2–2.7, p=0.002), adjusting for baseline characteristics. Arthralgia then worsened further over a year in the AI group. Menopausal symptom severity and existing joint-related comorbidity at baseline among women initiating AI were associated with more severe longitudinal arthralgia.
Patients initiating AI should be told about the timing of arthralgia over the first year of therapy, and advised that it does not appear to resolve over the course of a year. Menopausal symptoms and joint-related comorbidity at AI initiation can help identify patients at risk for developing AI-related arthralgia.
PMCID: PMC3687009  PMID: 23575918
Breast neoplasms; arthralgia; joint pain; aromatase inhibitors; postmenopause; longitudinal studies
12.  A history of health-related quality of life outcomes in psychiatry 
Health-related quality of life (HRQoL) is a multidimensional concept that includes subjective reports of symptoms, side effects, functioning in multiple life domains, and general perceptions of life satisfaction and quality. Rather than estimating it from external observations, interview, or clinical assessment, it is best measured by direct query. Due to a perception that respondents may not be reliable or credible, there has been some reluctance to use self-report outcomes in psychiatry. More recently, and increasingly, HRQoL assessment through direct patient query has become common when evaluating a range of psychiatric, psychological, and social therapies. With few exceptions, psychiatric patients are credible and reliable reporters of this information. This article summarizes studies that highlight the development, validation, and application of HRQoL measures in psychiatry. Thoughtful application of these tools in psychiatric research can provide a much-needed patient perspective in the future of comparative effectiveness research, patient-centered outcomes research, and clinical care.
PMCID: PMC4140507  PMID: 25152652
health-related quality of life; quality of life; psychiatric outcome; psychiatric symptom; patient-reported outcome
13.  Assessment of self-reported negative affect in the NIH Toolbox 
Psychiatry research  2012;206(1):88-97.
We report on the selection of self-report measures for inclusion in the NIH Toolbox that are suitable for assessing the full range of negative affect including sadness, fear, and anger. The Toolbox is intended to serve as a “core battery” of assessment tools for cognition, sensation, motor function, and emotional health that will help to overcome the lack of consistency in measures used across epidemiological, observational, and intervention studies. A secondary goal of the NIH Toolbox is the identification of measures that are flexible, efficient, and precise, an agenda best fulfilled by the use of item banks calibrated with models from item response theory (IRT) and suitable for adaptive testing. Results from a sample of 1,763 respondents supported use of the adult and pediatric item banks for emotional distress from the Patient-Reported Outcomes Measurement Information System (PROMIS®) as a starting point for capturing the full range of negative affect in healthy individuals. Content coverage for the adult Toolbox was also enhanced by the development of a scale for somatic arousal using items from the Mood and Anxiety Symptom Questionnaire (MASQ) and scales for hostility and physical aggression using items from the Buss-Perry Aggression Questionnaire (BPAQ).
PMCID: PMC3561498  PMID: 23083918
sadness; fear; anger; item response theory; measurement
14.  The Comparability of English, French and Dutch Scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F): An Assessment of Differential Item Functioning in Patients with Systemic Sclerosis 
PLoS ONE  2014;9(3):e91979.
The Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F) is commonly used to assess fatigue in rheumatic diseases, and has shown to discriminate better across levels of the fatigue spectrum than other commonly used measures. The aim of this study was to assess the cross-language measurement equivalence of the English, French, and Dutch versions of the FACIT-F in systemic sclerosis (SSc) patients.
The FACIT-F was completed by 871 English-speaking Canadian, 238 French-speaking Canadian and 230 Dutch SSc patients. Confirmatory factor analysis was used to assess the factor structure in the three samples. The Multiple-Indicator Multiple-Cause (MIMIC) model was utilized to assess differential item functioning (DIF), comparing English versus French and versus Dutch patient responses separately.
A unidimensional factor model showed good fit in all samples. Comparing French versus English patients, statistically significant, but small-magnitude DIF was found for 3 of 13 items. French patients had 0.04 of a standard deviation (SD) lower latent fatigue scores than English patients and there was an increase of only 0.03 SD after accounting for DIF. For the Dutch versus English comparison, 4 items showed small, but statistically significant, DIF. Dutch patients had 0.20 SD lower latent fatigue scores than English patients. After correcting for DIF, there was a reduction of 0.16 SD in this difference.
There was statistically significant DIF in several items, but the overall effect on fatigue scores was minimal. English, French and Dutch versions of the FACIT-F can be reasonably treated as having equivalent scoring metrics.
PMCID: PMC3956818  PMID: 24638101
15.  Emotion assessment using the NIH Toolbox 
Neurology  2013;80(11 Suppl 3):S76-S86.
One of the goals of the NIH Toolbox for Assessment of Neurological and Behavioral Function was to identify or develop brief measures of emotion for use in prospective epidemiologic and clinical research. Emotional health has significant links to physical health and exerts a powerful effect on perceptions of life quality. Based on an extensive literature review and expert input, the Emotion team identified 4 central subdomains: Negative Affect, Psychological Well-Being, Stress and Self-Efficacy, and Social Relationships. A subsequent psychometric review identified several existing self-report and proxy measures of these subdomains with measurement characteristics that met the NIH Toolbox criteria. In cases where adequate measures did not exist, robust item banks were developed to assess concepts of interest. A population-weighted sample was recruited by an online survey panel to provide initial item calibration and measure validation data. Participants aged 8 to 85 years completed self-report measures whereas parents/guardians responded for children aged 3 to 12 years. Data were analyzed using a combination of classic test theory and item response theory methods, yielding efficient measures of emotional health concepts. An overview of the development of the NIH Toolbox Emotion battery is presented along with preliminary results. Norming activities led to further refinement of the battery, thus enhancing the robustness of emotional health measurement for researchers using the NIH Toolbox.
PMCID: PMC3662334  PMID: 23479549
16.  Assessing Social Support, Companionship, and Distress: NIH Toolbox Adult Social Relationship Scales 
The quality of our daily social interactions – including perceptions of support, feelings of loneliness, and distress stemming from negative social exchanges – influence physical health and well-being. Despite the importance of social relationships, brief yet precise, unidimensional scales that assess key aspects of social relationship quality are lacking. As part of the NIH Toolbox for the Assessment of Neurological and Behavioral Function, we developed brief self-report scales designed to assess aspects of social support, companionship, and social distress across age cohorts. This report details the development and psychometric testing of the adult NIH Toolbox Social Relationship scales.
Social relationship concepts were selected, and item sets were developed and revised based on expert feedback and literature review. Items were then tested across a community-dwelling U.S. internet panel sample of adults aged 18 and above (N=692) using traditional (classic) psychometric methods and item response theory (IRT) approaches to identify items for inclusion in 5–8 item unidimensional scales. Finally, concurrent validity of the newly-developed scales was evaluated with respect to their inter-relationships with classic social relationship validation instruments.
Results provide support for the internal reliability and concurrent validity of resulting self-report scales assessing Emotional Support, Instrumental Support, Friendship, Loneliness, Perceived Rejection, and Perceived Hostility.
These brief social relationship scales provide the pragmatic utility and enhanced precision needed to promote future epidemiological and social neuroscience research on the impact of social relationships on physical and emotional health outcomes.
PMCID: PMC3759525  PMID: 23437856
social support; companionship; loneliness; social distress
17.  Comparison Of Methods To Estimate Health State Utilities For Ovarian Cancer Using Quality of Life Data: A Gynecologic Oncology Group Study 
Gynecologic oncology  2012;128(2):175-180.
Cost-effectiveness/cost-utility analyses are increasingly needed to inform decisions about care. Algorithms have been developed using the Functional Assessment of Cancer Therapy (FACT) quality of life instrument to estimate utility weights for cost analyses. This study was designed to compare these algorithms in the setting of ovarian cancer.
GOG-0152 was a 550-patient randomized phase III trial of interval cytoreduction, and GOG-0172 was a 415-patient randomized phase III trial comparing intravenous versus intraperitoneal therapy among women with advanced ovarian cancer. QOL data were collected via the FACT at four time points in each study. Two published mapping algorithms (Cheung and Dobrez) and a linear transformation method were applied to these data. The agreement between measures was assessed by the concordance correlation coefficient (rCCC), and paired t-tests were used to compare means.
While agreement between the estimation algorithms was good (ranged from 0.72 to 0.81), there were statistically significant (p<0.001) and clinically meaningful differences between the scores: mean scores were higher with Dobrez than with Cheung or the linear transformation method.. Scores were also statistically significantly different (p<0.001) between studies.
In the absence of prospectively collected utility data, the use of mapping algorithms is feasible, however, the optimal algorithm is not clear. There were significant differences between studies, which highlights the need for validation of these algorithms in specific settings. If cost analyses incorporate mapping algorithms to obtain utility estimates, investigators should take the variability into account.
PMCID: PMC3552113  PMID: 23123576
health utilities; ovarian cancer; quality of life; methodology; comparative effectiveness research
18.  General Population Norms for the Functional Assessment of Cancer Therapy – Kidney Symptom Index (FKSI) 
Cancer  2012;119(2):429-437.
Metastatic renal cell cancer is associated with poor long-term survival and has no cure. Traditional clinical endpoints are best supplemented by patient-reported outcomes designed to assess symptoms and function. We obtained normative data on the NCCN - Functional Assessment of Cancer Therapy – Kidney Symptom Index (NFKSI) to aid in score interpretation and planning of future trials.
General population data were obtained from 2000 respondents, who completed the NFKSI-19, as well the SF-36 and the PROMIS-29, both general health status measures. Basic demographic and self-reported comorbidity data were also collected.
The sample was 50% female, 85.7% Caucasian, with an equal distribution across age bands 18–75+. Most respondents (62.8%) had more than a high school education and reported an ECOG performance status of normal activity without symptoms (63.4%). Score distributions on the NFKSI-19, its subscales, and individual items are summarized.
The NFKSI-19 and its subscales now have scores for the general US population, allowing comparability to generic questionnaires such as the SF-36 and PROMIS-29. These data can be used to guide treatment expectations and plan future comparative effectiveness research using the scales.
PMCID: PMC3470751  PMID: 22778010
quality of life; questionnaire; renal cell cancer; general population
19.  Neuro-QOL: quality of life item banks for adults with neurological disorders: item development and calibrations based upon clinical and general population testing 
Neuro-QOL provides a clinically relevant and psychometrically robust health-related quality of life (HRQL) assessment tool for both adults and children with common neurological disorders. We now report the psychometric results for the adult tools.
An extensive research, survey and consensus process was used to produce a list of 5 priority adult neurological conditions (stroke, multiple sclerosis, Parkinson’s disease, epilepsy and ALS). We identified relevant health related quality of life (HRQL) domains through multiple methods and data sources including a comprehensive review of the literature and literature search, expert interviews and surveys and patient and caregiver focus groups. The final domain framework consisted of 17 domains of Physical, Mental and Social health. There were five phases of item development: (1) identification of 3,482 extant items, (2) item classification and selection, (3) item review and revision, (4) cognitive interviews with 63 patients to assess their understanding of individual items and (5) field testing of 432 representative items.
Participants and Procedures
Participants were drawn from the US general population and clinical settings, and included both English and Spanish speaking subjects (N = 3,246). Confirmatory factor analysis (CFA) was used to evaluate the dimensionality of unidimensional domains. Where the domain structure was previously unknown, the dataset was split and first analyzed with exploratory factor analysis and then CFA. Samejima’s graded response model (GRM) was used to calculate IRT parameters. We further evaluated differential item functioning (DIF) on gender, education and age.
Thirteen unidimensional calibrated item banks consisting of 297 items were developed. All of the tested item banks had high reliability and few or no locally dependent items. The range of item slopes and thresholds with good information are reported for each of the item banks. The banks can support CAT and the development of short forms.
The Neuro-QOL measurement system provides item banks and short forms that enable PRO measurement in neurological research, minimizes patient burden and can be used to create multiple instrument types minimizing standard error. The 17 adult measures include 13 calibrated item banks, 3 item pools available for calibration work by others, and 1 stand-alone scale (index). The Neuro-QOL instruments provide a “common metric” of representative concepts for use across patient groups in different studies.
PMCID: PMC3889669  PMID: 21874314
Outcome measures; Quality of life; Neurological disorders; Computerized adaptive testing, item banking
20.  Parent-perceived child cognitive function: results from a sample drawn from the US general population 
This paper reports the development and evaluation of a perceived cognitive function (pedsPCF) item bank reported by parents of the pediatric US general population.
Based on feedback from clinicians, parents, and children, we developed a scale sampling concerns related to children’s cognitive functioning. We administered the scale to 1,409 parents of children aged 7–17 years; of them, 319 had a neurological diagnosis. Dimensionality of the pedsPCF was evaluated via factor analyses and its clinical utility studied by comparing parent ratings in patient groups and symptom cluster defined by the Child Behavior Checklist (CBCL).
Forty-four of 45 items met criteria for unidimensionality. The pedsPCF significantly differentiated samples defined by medication use, repeated grades, special education status, neurologic diagnosis, and relevant symptom clusters with large effect sizes (>0.8). It can predicted children symptoms with the correction rates ranging 79–89%.
We have provided empirical support for the unidimensionality of the pedsPCF item bank and evidence for its potential clinical utility. The pedsPCF is a promising measurement tool to screen children for further comprehensive cognitive tests.
PMCID: PMC3885608  PMID: 20652814
Perceived cognitive function; Children; Brain tumor; Neuro-oncology; Item bank
21.  Measurement of Fatigue in Cancer, Stroke, and HIV Using the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) Scale 
Given the importance of fatigue in cancer, stroke and HIV, we sought to assess the measurement properties of a single, well-described fatigue scale in these populations. We hypothesized that the psychometric properties of the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) subscale would be favorable and that the scale could serve as a useful indicator of fatigue in these populations.
Patients were eligible for the study if they were outpatients, aged 18 or older, with a diagnosis of cancer (n=297), stroke (n=51), or HIV/AIDS (n=51). All participants were able to understand and speak English. Patients answered study-related questions, including the FACIT-F using a touch-screen laptop, assisted by the research assistant as necessary. Clinical information was abstracted from patients’ medical records.
Item-level statistics on the FACIT-F were similar across the groups and internal consistency reliability was uniformly high (α>0.91). Correlations with performance status ratings were statistically significant across the groups (range r=−0.28 to −0.80). Fatigue scores were moderately to highly correlated with general quality of life (range r=0.66–0.80) in patients with cancer, stroke, and HIV. Divergent validity was supported in low correlations with variables not expected to correlate with fatigue.
Originally developed to assess cancer-related fatigue, the FACIT-F has utility as a measure of fatigue in other populations, such as stroke and HIV. Ongoing research will soon allow for comparison of FACIT-F scores to those obtained using the fatigue measures from the Patient-Reported Outcomes Measurement Information System (PROMIS®; initiative.
PMCID: PMC3534851  PMID: 23272990
fatigue; assessment; psychometrics; cancer; stroke; HIV
Stroke is a leading cause of long-term disability in the USA; however, we have an incomplete understanding of how stroke affects long-term quality of life.
We report here findings from focus groups with 9 long-term stroke survivors and 6 caregivers addressing patients’ post-stroke quality of life.
Key themes identified by patients were: social support, coping mechanisms, communication, physical functioning and independence. Role changes in patients were important to caregivers. Much of the discussion with patients and caregivers described specific ways in which the stroke altered social relationships.
These findings are consistent with prior research indicating the importance of social factors to quality of life following stroke. Our findings suggest that measures of stroke-related quality of life should include assessment of social function and social support.
PMCID: PMC3869390  PMID: 18758667
stroke; quality of life; qualitative analysis; social function
23.  The case for an international patient-reported outcomes measurement information system (PROMIS®) initiative 
Patient-reported outcomes (PROs) play an increasingly important role in clinical practice and research. Modern psychometric methods such as item response theory (IRT) enable the creation of item banks that support fixed-length forms as well as computerized adaptive testing (CAT), often resulting in improved measurement precision and responsiveness. Here we describe and discuss the case for developing an international core set of PROs building from the US PROMIS® network.
PROMIS is a U.S.-based cooperative group of research sites and centers of excellence convened to develop and standardize PRO measures across studies and settings. If extended to a global collaboration, PROMIS has the potential to transform PRO measurement by creating a shared, unifying terminology and metric for reporting of common symptoms and functional life domains. Extending a common set of standardized PRO measures to the international community offers great potential for improving patient-centered research, clinical trials reporting, population monitoring, and health care worldwide. Benefits of such standardization include the possibility of: international syntheses (such as meta-analyses) of research findings; international population monitoring and policy development; health services administrators and planners access to relevant information on the populations they serve; better assessment and monitoring of patients by providers; and improved shared decision making.
The goal of the current PROMIS International initiative is to ensure that item banks are translated and culturally adapted for use in adults and children in as many countries as possible. The process includes 3 key steps: translation/cultural adaptation, calibration, and validation. A universal translation, an approach focusing on commonalities, rather than differences across versions developed in regions or countries speaking the same language, is proposed to ensure conceptual equivalence for all items. International item calibration using nationally representative samples of adults and children within countries is essential to demonstrate that all items possess expected strong measurement properties. Finally, it is important to demonstrate that the PROMIS measures are valid, reliable and responsive to change when used in an international context.
IRT item banking will allow for tailoring within countries and facilitate growth and evolution of PROs through contributions from the international measurement community. A number of opportunities and challenges of international development of PROs item banks are discussed.
PMCID: PMC3879205  PMID: 24359143
Patient-reported outcomes; Health-related quality of life research; Patients’ experiences; Questionnaires; Cross-cultural equivalence; Health information systems; Clinical decision making; Comparative effectiveness research; Patient empowerment; Cross-national comparisons
24.  Development and Validation of a Symptom Index for Advanced Hepatobiliary and Pancreatic Cancers: The NCCN-FACT Hepatobiliary-Pancreatic Symptom Index (NFHSI) 
Cancer  2012;118(23):5997-6004.
The 45-item Functional Assessment of Cancer Therapy – Hepatobiliary (FACT-Hep) questionnaire assesses health-related quality of life in patients with liver, bile duct and pancreatic cancers. Although the FACT-Hep was initially derived from patient input, we sought to verify adequate coverage of items by soliciting open-ended input from patients with advanced disease.
As part of a larger study in collaboration with the NCCN, 50 people (60% male, 80% Caucasian, average age 60.4 yrs) with Stage 3 or 4 hepatobiliary or pancreatic cancer were recruited. Participants generated and ranked up to 10 important symptoms and concerns that physicians should monitor when assessing the value of chemotherapy. Patients were also able to provide open-ended, qualitative information that was evaluated systematically. Ten expert physicians also provided input on priority symptoms.
The resulting 18-item NCCN-FHSI (NFHSI-18) demonstrated high internal consistency (α = 0.89) and moderate to strong correlations with measures of physical well-being (ρ = 0.76), emotional well-being (ρ = 0.52), and functional well-being (ρ = 0.57). Scores on the NFHSI-18 were also highly correlated with the original hepatobiliary scale of the FACT-Hep (ρ = 0.82; all p<0.001). Compared to patients with better performance status, patients with poor performance status had worse NFHSI-18 symptom scores, F (3, 47) = 9.74; p=0.0003.
The NFHSI 18 assesses symptoms of importance to patients with hepatobiliary and pancreatic cancers and-demonstrates promising measurement properties. The scale is a good candidate for brief symptom assessment in clinical trials.
PMCID: PMC3424375  PMID: 22605658
advanced cancer; symptom assessment; hepatobiliary cancer; pancreatic cancer
25.  NUTORC—a transdisciplinary health services and outcomes research team in transplantation 
The field of solid organ transplantation has historically concentrated research efforts on basic science and translational studies. However, there has been increasing interest in health services and outcomes research. The aim was to build an effective and sustainable, inter- and transdisciplinary health services and outcomes research team (NUTORC), that leveraged institutional strengths in social science, engineering, and management disciplines, coupled with an international recognized transplant program. In 2008, leading methodological experts across the university were identified and intramural funding was obtained for the NUTORC initiative. Inter- and transdisciplinary collaborative teams were created across departments and schools within the university. Within 3 years, NUTORC became fiscally sustainable, yielding more than tenfold return of the initial investment. Academic productivity included funding for 39 grants, publication of 60 manuscripts, and 166 national presentations. Sustainable educational opportunities for students were created. Inter- and transdisciplinary health services and outcomes research in transplant can be innovative and sustainable.
PMCID: PMC3647618  PMID: 23667403
Transdisciplinary research teams; Health Services and Outcomes Research; Educational opportunities; Academic productivity; Sustainable research efforts

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