Systematic review of the Multidimensional Fatigue Symptom Inventory-Short Form

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1 DOI /s REVIEW ARTICLE Systematic review of the Multidimensional Fatigue Symptom Inventory-Short Form Kristine A. Donovan & Kevin D. Stein & Morgan Lee & Corinne R. Leach & Onaedo Ilozumba & Paul B. Jacobsen Received: 5 May 2014 /Accepted: 5 August 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract Purpose Fatigue is a subjective complaint that is believed to be multifactorial in its etiology and multidimensional in its expression. Fatigue may be experienced by individuals in different dimensions as physical, mental, and emotional tiredness. The purposes of this study were to review and characterize the use of the 30-item Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) in published studies and to evaluate the available evidence for its psychometric properties. Methods A systematic review was conducted to identify published articles reporting results for the MFSI-SF. Data were analyzed to characterize internal consistency reliability of multi-item MFSI-SF scales and test-retest reliability. Correlation coefficients were summarized to characterize concurrent, convergent, and divergent validity. Standardized effect sizes were calculated to characterize the discriminative validity of the MFSI-SF and its sensitivity to change. Results Seventy articles were identified. Sample sizes reported ranged from 10 to 529 and nearly half consisted exclusively of females. More than half the samples were composed of K. A. Donovan (*): P. B. Jacobsen Health Outcomes and Behavior Program, Moffitt Cancer Center and Research Institute, Magnolia Drive, MRC-SCM, Tampa, FL 33612, USA kristine.donovan@moffitt.org K. D. Stein: C. R. Leach Behavioral Research Center, Intramural Research Department, American Cancer Society, Atlanta, GA, USA K. D. Stein: C. R. Leach : O. Ilozumba Department of Behavioral Sciences and Health Education, Emory University Rollins School of Public Health, Atlanta, GA, USA M. Lee Department of Psychology, University of South Florida, Tampa, FL, USA cancer patients; of those, 59 % were breast cancer patients. Mean alpha coefficients for MFSI-SF fatigue subscales ranged from 0.84 for physical fatigue to 0.93 for general fatigue. The MFSI-SF demonstrated moderate test-retest reliability in a small number of studies. Correlations with other fatigue and vitality measures were moderate to large in size and in the expected direction. The MFSI-SF fatigue subscales were positively correlated with measures of distress, depressive, and anxious symptoms. Effect sizes for discriminative validity ranged from medium to large, while effect sizes for sensitivity to change ranged from small to large. Conclusions Findings demonstrate the positive psychometric properties of the MFSI-SF, provide evidence for its usefulness in medically ill and nonmedically ill individuals, and support its use in future studies. Keywords Fatigue. Chronic illness. Cancer. Multidimensional Fatigue Symptom Inventory Introduction Fatigue is generally defined as a sense of persistent tiredness or exhaustion that is often distressing to the individual. It is a common subjective complaint among persons with chronic illness, including cancer, and among persons who are healthy or acutely ill. Accordingly, the etiology of fatigue is believed to be multifactorial [1]. Fatigue is often described by those who experience it in terms of physical, mental, and emotional tiredness. These sensations may be sufficiently consistent as to be characterized as unidimensional or, conversely, as sufficiently distinct in their expression as to be characterized as different dimensions of fatigue [2]. This multidimensional characterization of fatigue is evidenced by the large number and variety of multidimensional fatigue measures currently available [3 5].

2 Although the availability of multidimensional fatigue measures heralds the wide acceptance of fatigue as multidimensional in nature, it also makes the decision of which measure to use and when to use it a challenge. As we have previously noted [6], the choice depends on several considerations [4, 5, 7]. These include what dimensions of fatigue one wishes to measure, the practical aspects of any one measure s usability, the measure s clinical and/or research utility, and whether the scale possesses robust psychometric properties, including the strength of the evidence for the measure s reliability and validity and the population(s) on which the psychometric data are based [8]. The Multidimensional Fatigue Symptom Inventory-Short Form [9] (MFSI-SF), first published in 1998, is a 30-item selfreport measure derived from an initial pool of 83 items designed to assess five empirically derived dimensions of fatigue: general fatigue, physical fatigue, emotional fatigue, mental fatigue, and vigor. A total fatigue score may be calculated by subtracting the vigor subscale score from the sum of the four fatigue subscales. The psychometric properties of the MFSI-SF were originally established in women with a diagnosis of breast cancer and women with no history of cancer. The measure was further validated in a study of males and females with a variety of different cancer diagnoses [10]. Since its development, the MFSI-SF has been used to describe fatigue in a variety of clinical and nonclinical populations and as a patient-reported outcome measure in clinical studies. A cursory review of the literature demonstrates that the MFSI-SF is a widely used multidimensional measure of fatigue. We believe that as the MFSI-SF continues to be used and the data based on its use accumulate, it is important to examine how it has been used subsequent to the original validation studies and to characterize the evidence base supporting its current and future use. Toward that end, the aims of this paper are to review and characterize the use of the MFSI-SF in published studies and to evaluate the available evidence for its psychometric properties. To accomplish this, we conducted a systematic review of the literature to identify published studies that reported results on the MFSI-SF. These data were used to describe the characteristics of studies that have used the MFSI-SF and were analyzed based on statistical considerations to summarize evidence regarding the reliability, validity, and sensitivity to change of the MFSI-SF. Methods Search and selection strategy The identification of relevant publications began with an electronic search of Web of Science to identify journal articles citing one of two published papers that described the development and early validation of the MFSI-SF [9, 10]. We also searched Medline, PsycINFO, and Cumulative Index to Nursing and Allied Health (CINAHL) from 1998, the year the MFSI-SF was first published, through December 2013 using the search term Multidimensional Fatigue Symptom Inventory. Study abstracts were screened based on two eligibility criteria. The first criterion was that each study must have been published in a peer-reviewed English language journal. The second was that each study had to report results based on the administration of the MFSI-SF. Studies in which fatigue was assessed without using the MFSI-SF were excluded. Similarly, reviews summarizing results of published studies of fatigue were excluded. Reference lists from studies retrieved also were reviewed to ensure that all possible studies that derived empirical results for the MFSI-SF were captured. Discrepancies among reviewers in the selection of studies were resolved by discussions designed to yield consensus. Bias was reduced by conducting a comprehensive search of published studies in several electronic databases and searching reference lists of published reviews. Review and data extraction Each member of a pair of authors separately reviewed the studies that met eligibility criteria and collected relevant information from each of the studies using a standardized form to ensure consistency within as well as between paired authors. As with article selection, discrepancies in the information extracted were resolved through consensus discussion. The information included participants demographic and clinical characteristics, the purpose and design of the study, and the MFSI-SF subscales for which results were reported. In addition, studies were reviewed to determine if they contained results bearing on the reliability and validity of the MFSI-SF, and if so, this information also was collected. With respect to reliability, evidence for the internal consistency and test-retest reliability of the instrument was identified. With respect to construct validity, evidence of structural, concurrent, convergent, divergent, and discriminative validity was extracted. For purposes of this review, we considered structural validity to be the extent to which the original factor structure of the MFSI- SF was reproducible, concurrent validity to be the degree to which MFSI-SF scales are correlated with other published measures of fatigue, convergent validity to be the degree to which MFSI-SF scales correlated with measures of conceptually related constructs, and divergent validity to be the degree to which MFSI-SF scales either negatively correlated or did not correlate with measures of constructs believed to be conceptually distinct from fatigue. Discriminative validity was evident if MFSI-SF scores of one group differed as expected from those of a comparison group. Finally, evidence of the sensitivity to change of the MFSI-SF as a result of an intervention or disease treatment likely to alter the level of fatigue was extracted.

3 Statistical analysis Descriptive statistics, including means and percentages, were calculated to characterize the samples identified in the relevant articles. The psychometric properties were evaluated using information available from the published articles. Cronbach s alpha coefficients and correlation coefficients, when reported, were used to assess the internal consistency reliability and test-retest reliability of the MFSI-SF subscales, respectively. Correlation coefficients between MFSI-SF subscales and other published measures were examined when available to characterize the concurrent, convergent, and divergent validity of the MFSI-SF. Summary statistics in the form of mean correlation coefficients with two-sided 95 % confidence intervals for the mean were calculated in some instances for illustrative purposes. Consistent with Cohen [11], correlation coefficients in the order of 0.10 were considered small, those of 0.30 moderate, and those of 0.50 large. Finally, Cohen s d [11], a measure of effect size, was calculated to characterize the discriminative validity of the MFSI-SF and a standardized effect size [12] using baseline and follow-up scores. The standard deviation of baseline scores was calculated to characterize the sensitivity of the MFSI-SF to change. An effect size of 0.20 to 0.30 was considered a small effect, around 0.50 a medium effect, and around 0.80 a large effect [11]. When effect sizes were calculated by the authors of the published studies, we did not recalculate these statistics but reproduced them in our results. Results Search results and characteristics of selected studies A total of 431 abstracts were screened, and the complete texts of 178 studies were retrieved and reviewed (see Fig. 1). Ultimately, we identified 70 articles published between 1998 and 2013 that reported results on the administration of the MFSI-SF; this includes the 1998 study [9]of the psychometric properties of the instrument (see Table 1). Forty-four studies involved cancer patients; of these, 26 studies were exclusively of women with a diagnosis of breast cancer, and 15 were of a mix of cancer types, including three studies [13 15] that included women with gynecologic cancer. Among studies of cancer patients, 11 studies included noncancer. Various points in the cancer treatment trajectory were represented; results are reported for patients who completed the MFSI-SF before beginning treatment, while undergoing treatment, after having completed treatment, and well into posttreatment survivorship.whilethemfsi-sfseemstohavebeenusedpredominantly to assess fatigue in cancer patients, especially breast 431 potentially relevant abstracts and cross references identified via Web of Science, Medline, PsycINFO, CINAHL, and manual search of reference lists 188 duplicate abstracts 243 abstracts screened 178 studies obtained for further assessment of eligibility 70 studies included in present review Fig. 1 Study identification 65 abstracts excluded (e.g., fatigue not assessed with MFSI-SF, reviews of fatigue measures, reviews of cancerrelated fatigue 108 full-text articles excluded (e.g., fatigue not assessed with MFSI-SF, MFSI-SF data not reported sufficient for review cancer patients, results also have been reported for a variety of health conditions, including, but not limited to, fibromyalgia [16], osteoarthritis [17], stroke [18], and hypertension [19, 20], and in kidney transplant candidates [21]. We also identified six studies [22 27] that used the MFSI-SF exclusively to assess fatigue in individuals with no reported health conditions. The MFSI-SF was administered across a range of study designs. Thirty-five studies employed a cross-sectional design and 25 employed a longitudinal design. The MFSI-SF was also administered in ten randomized controlled trials. Thirty-one studies reported results on all five subscales of the MFSI-SF. Twenty studies reported results limited to total fatigue (sum of four fatigue subscales minus vigor subscale) while 17 studies reported on four or fewer subscales consistent with the purpose of the particular study; in those studies, the majority reported on the physical subscale of the MFSI-SF. Two studies, the original validation study of the MFSI-SF that led to the final 30-item version and a study [28]toestimatethe prevalence of severe fatigue according to draft International Statistical Classification of Disease and Related Health Problems-10 criteria for cancer-related fatigue, used the original 83-item version. Four studies reported results based on translations of the MFSI-SF into Chinese [29], German [30, 31], and Italian [23]. Two studies reported results based on modified approaches for scoring the MFSI-SF: One was the study [29] examining the psychometric properties of the Chinese version of the MFSI- SF in a patient sample of mixed cancer types that combined the physical and general subscales to create a new physical subscale. The other study [32] adapted the vigor subscale to assess energy in a study of healthy and recreationally active individuals.

4 Table 1 Characteristics of studies reporting results on the administration of the Multidimensional Fatigue Symptom Inventory-Short Form Authors Disease Position in disease/ treatment trajectory Study purpose Sample size Sex Age (mean and SD) (range) Design Scales reported in analyses Stein et al. [9] Breast cancer About to start treatment and posttreatment Broeckel et al. [40] Breast cancer At least 5 years postdiagnosis or recurrence Mantovani et al. [59] Mix of cancer types Histologically confirmed advanced stage tumor; signs of cancer-related anorexia/cachexia syndrome present Develop and validate a multidimensional measure of fatigue for use with cancer patients Examine characteristics and correlates of sexual functioning in long-term breast cancer survivors treated with chemotherapy compared to noncancer Test the efficacy and safety of an integrated treatment (pharmaconutritional, antioxidant, and drug) in advanced cancer patients with CACS/OS Stein et al. [10] Mix of cancer types About to start chemotherapy Evaluate the factorial and construct validity of the MFSI-SF de Leeuw, Studts and Carlson [41] Helgeson and Tomich [68] Temporomandibular disorders Diagnosed with temporomandibular disorder;atleast 3 months of pain; reported pain in past month Investigate the presence and magnitude of self-reported fatigue and fatigue-related symptoms and determine whether fatigue can be distinguished as a unique clinical symptom in a sample of patients diagnosed with chronic temporomandibular joint or masticatory muscle pain Breast cancer years post-diagnosis Evaluate the long-term impact of breast cancer on QOL by comparing disease-free survivors, survivors w/ a recurrence, and healthy Lim et al. [24] None (nonclinical sample) NA Examine the associations among obesity, depressive symptoms, cytokine levels, and multidimensional fatigue symptoms among asymptomatic and healthy individuals Liu et al. [63] Breast cancer Newly diagnosed; scheduled to receive at least 4 3 week cycles of adjuvant or neo-adjuvant anthracycline-based chemotherapy Investigate the association between fatigue and light exposure among patients with breast cancer 275 patients; 70 noncancer 58 patients; 61 noncancer 100 % female Active treatment 53.6 (12.2) (28-83), posttreatment 54.1 (13.7) (32 86), noncancer 53.4 (11.5) (34 77) 100 % female Patients 56.2 (8.8), noncancer 54.6 (8.9) Longitudinal Emotional, general, mental, physical, vigor Cross-sectional Total 25 patients 52 % female 58.2 (9.0) Longitudinal Total, vigor 304 patients 80 % female 54.9 (11.5) (28 88) Cross-sectional Total, emotional, 55 patients; 55 healthy 267 disease free patients, 37 patients with a recurrence, 187 noncancer Patients: 96 % female; healthy : 96 % female Patients 32.3 (12.5), healthy 32.6 (12.7) 100 % female Disease free patients 54.4, patients with a recurrence 51.2, 53.2 Cross-sectional Emotional, general, mental, physical, vigor Longitudinal General, mental, physical 70 individuals 51 % female 36 (7.8) Cross-sectional Total, emotional, 63 patients 100 % female 52.0 (10.5) Longitudinal Total, emotional, physical, Vigor Mills et al. [65] Breast cancer 29 patients 100 % female 49.5 (11) Longitudinal Total

5 Table 1 (continued) Authors Disease Position in disease/ treatment trajectory Study purpose Sample size Sex Age (mean and SD) (range) Design Scales reported in analyses Stage I-IIIA and referred for adjuvant or neoadjuvant anthracycline-based chemotherapy Ancoli-Israel et al. [51] Breast cancer Scheduled to begin neoadjuvant chemotherapy or adjuvant chemotherapy Banthia et al., 2006[39] Breast cancer Post-treatment, between 1 month and 3 years previously Determine whether chemotherapy-induced changes in the inflammatory markers SICAM-1, VEGF, and IL-6 are associated with fatigue, depressed mood, and poorer quality of life. Examine sleep, fatigue, and circadian rhythms in breast cancer patients before start of chemotherapy Investigate correspondence between daily and weekly ratings of fatigue over 1 month period by fatigued breast cancer survivors (defined as 5+ score on MFSI general) Bardwell et al. [19] Hypertension NA Determine if SES partially explains ethnic disparities in fatigue Gramignano et al. [23] None (nonclinical sample) Active treatment Test efficacy and safety of L-carnitine supplementation in patients who had advanced cancer and developed fatigue, high blood levels of reactive oxygen species or both Mantovani et al. [61] Mix of cancer types Histologically confirmed advanced stage tumor; signs of cancer-related anorexia/cachexia syndrome present Prue et al. [13] Gynecologic cancers Various points but within mean of 3 months of starting treatment Siegel et al. [69] Chronic fatigue syndrome (CFS) Test the efficacy and safety of an integrated treatment (pharmaconutritional, antioxidant, and drug) in advanced cancer patients with CACS Explore incidence and magnitude of fatigue and determine acceptability of MFSI-SF with gynecologic cancer patients Diagnosis of CFS Compare clinical presentation of CFS patients with and without clinically reduced natural killer cell activity (NKCA) Thomas et al. [26] None (nonclinical sample) NA Examine how discrimination and ethnic identify relate to sleep architecture and fatigue Young and White [28] Breast cancer Completed curative treatment at least 6 months previously Estimate prevalence of severe fatigue according to draft ICD-10 criteria for cancer-related fatigue; identify prevalence and moderators of clinical syndrome 85 patients 100 % female 51.2 (10.0) (34 79) Cross-sectional Total, emotional, 25 patients 100 % female 53.7 (12.6) (32 83) Longitudinal Emotional, general, mental, physical, Vigor 40 African Americans, 64 Caucasian Americans 47 % female Range=25-52 Cross-sectional General 12 patients 83 % female 60 (9) (42 73) Longitudinal Total, emotional, 39 patients 41 % female 58.9 (9.1) Longitudinal Total 30 patients 100 % female 60.9 (13.5) (31-84) Cross-sectional Total, emotional, 22 low NKCA patients, 19 normal NKCA patients 37 African Americans, 56 Caucasian Americans 100 % female Low NKCA 45.3 (9.6) (36 55), normal NKCA 43.5 (8.9) (35 52) African Americans: 49 % female; Caucasian Americans: 39 % female African Americans 38.1 (1.4) (37 40), Caucasian Americans 35.6 (1.0) (35 37) Cross-sectional Mental Cross-sectional Emotional, general, mental, physical, vigor 69 patients 100 % female 59 (26 81) Cross-sectional Global, affective, behavioral, cognitive, somatic, vigor 51 patients 88 % female Cross-sectional

6 Table 1 (continued) Authors Disease Position in disease/ treatment trajectory Study purpose Sample size Sex Age (mean and SD) (range) Design Scales reported in analyses Balasubramaniam et al. [70] Temporomandibular disorders in fibromyalgia or failed back syndrome At least 6 months post-diagnosis of fibromyalgia or failed back syndrome Determine prevalence of temporomandibular disorders and evaluate psychosocial domains in patients with fibromyalgia compared with patients with failed back syndrome Feuerstein et al. [71] Brain tumor Completed primary treatment Investigate role of both non-modifiable and modifiable factors in brain tumor survivors and their association to work limitations Mead et al. [18] Stroke Post-stroke Identify which currently available fatigue scale is most valid, feasible, and reliable in stroke patients Clayton, Dudley and Musters [43] Collado-Hidalgo et al. [72] Breast cancer 2 or more years post-treatment Investigate how fatigue and communication are related to survivor uncertainty and mood state, and survivor perception of patient-centered communication for women with varying fatigue levels Breast cancer 1 to 5 years post-diagnosis; completed primary treatment Examine single-nucleotide polymorphisms in promoters of cytokine genes as genetic risk factors for cytokine-related fatigue in fatigued and nonfatigued breast cancer survivors Hansen et al. [73] Breast cancer Completed primary treatment Determine whether physical fatigue, depression, anxiety, and cognitive limitations are differentially associated with work limitations in breast cancer survivors versus non-cancer Mantovani et al. [60] Mix of cancer types Histologically confirmed advanced stage tumor; signs of cancer-related anorexia/cachexia syndrome present Phase III randomized trail to establish the most effective and safest treatment to improve key primary endpoints of CACS: increase of LBM, decrease of REE, and improvement of fatigue. Secondary endpoints also evaluated. Strigo et al. [74] Major depressive disorder Unmedicated for depression Examine hypothesis that young adults with MDD would show increased affective bias to painful and nonpainful experimental pain stimuli 95 patients; 131 noncancer T1=55 patients; T2=51 patients Patients: 59 % female; noncancer : 79 % female Fibromyalgia patients 52.2 (7.8), failed back syndrome patients 50.0 (9.1) brain tumor=20 29: 13.7 %, 30 39: 22.1 %, 40 49: 34.7 %, 50 59: 25.3 %, 60 70: 4.2 %; noncancer =20 29: 21.4 %, 30 39: 35.8 %, 40 49: 37.9 %, 50 59: 4.2 %, 60 70: 3.2 % (range=20 70) Cross-sectional Physical 44 % female Median=73 Longitudinal General 60 patients 100 % female (11.30) (31 87) Cross-sectional Total 33 fatigued patients; 14 non-fatigued patients 100 patients; 103 noncancer 100 % female Fatigued patients 54.1 (8.3), nonfatigued patients 61.1 (8.5) 100 % female Patients 49.5 (8.5), noncancer 39.8 (10.8) Cross-sectional General Cross-sectional Physical 125 patients 41 % female 61.9 (12.1) Longitudinal Total 15 patients, 15 healthy 80 % female Patients 24.1 (5.6) (19-30), healthy 23.9 (5.2) (19-29) Longitudinal Total Emotional, general, mental, physical, vigor

7 Table 1 (continued) Authors Disease Position in disease/ treatment trajectory Study purpose Sample size Sex Age (mean and SD) (range) Design Scales reported in analyses Banthia et al. [50] Breast cancer Post-treatment Examine age, cancer stage, sleep quality and depressed mood as predictors of 5 dimensions of fatigue in fatigued breast cancer survivors (defined as 5+ score on MFSI general) Calvio et al. [34] Malignant brain tumor 0-27 (mean=4) years post-diagnosis Günaydin et al. [45] Ankylosing spondylitis Disease duration: mean (10.3), range (1-35) Krummenacher et al. [30] Venous thromboembolism (VTE) At least 3 months after an objectively diagnosed venous thromboembolic event; scheduled for outpatient thrombophilia work-up Liu et al. [48] Breast cancer Newly diagnosed; scheduled to receive at least 4 3 week cycles of adjuvant or neo-adjuvant anthracyclinebased chemotherapy Lukas et al. [31] Deep vein thrombosis (DVT) and pulmonary embolism (PE) Roepke et al. [36] Alzheimer s caregivers and elderly non-caregiver Outpatient with objectively diagnosed venous thrombotic event (DVT and/or PE) Schmidtetal.[75] Masticatory muscle pain Diagnosis of pain for at least 2 months Calvio et al. [76] Breast cancer 1-10 (mean=3) years post primary treatment Investigate perceived cognitive function in employed malignant brain tumor survivors relative to healthy group of workers Evaluate the frequency and multidimensional nature of fatigue and identify associations with demographic, diseasespecific, and other variables (e.g. depression, sleep disturbance in AS patients Investigate the associations of subjective sleep quality, fatigue, and vital exhaustion with platelet count in VTE patients Explore associations between sleep disturbance/fatigue/ depression symptom cluster categories before treatment and longitudinal profiles of the symptoms during chemotherapy Investigate relationships between QOL, psychological distress (anxiety and depression), and fatigue in outpatients with a previous DVT and/or PE NA Examine whether personal mastery moderates relationship between caregiver status and fatigue Compare emotional reactivity and physiological response in masticatory muscle pain patients vs. pain-free Investigate relationship between perceived cognitive function at work and more generic performance-based neuropsychological measures of these functions 70 patients 100 % female 52.5 (12.2) (32 83) Cross-sectional Emotional, general, mental, physical, vigor 113 patients; 123 noncancer Patients: 65 % female; noncancer : 73 % female NR Cross-sectional Physical 62 patients 16 % female 39.6 (10.3) Cross-sectional Total, emotional, 205 patients 45 % female 47.2 (14.8) (18 80) Cross-sectional Total, emotional, 76 patients 100 % female 51.1 (9.1) Longitudinal Total 205 patients 45 % female 47.4 (14.9) Cross-sectional Total, emotional, 73 caregivers; 41 non-caregivers 22 patients; 23 healthy 122 patients; 113 noncancer Caregivers: 74 % female; non-caregivers: 78 % female Caregivers 72.2 (9.6) (63 82), noncaregivers 68.4 (6.7) (62 75) 100 % female Patients 41.0 (12.6) (28 54) Controls: Matched±5 100 % female Patients 44.9 (9.5), noncancer 39.2 (11.9) Cross-sectional Total, emotional, Cross-sectional Emotional, general, mental, physical, vigor Cross-sectional Physical

8 Table 1 (continued) Authors Disease Position in disease/ treatment trajectory Study purpose Sample size Sex Age (mean and SD) (range) Design Scales reported in analyses and work output in occupationally active breast cancer survivors relative to non-cancer control group Lee et al. [77] Sleep apnea Not specified Examine the relationship between the Psychomotor Vigilance Task (PVT) and subjective fatigue Mantovani et al. [57] Mix of cancer types Histologically confirmed advanced stage tumor; signs of cancer-related anorexia/cachexia syndrome present Mantovani et al. [58] Mix of cancer types Histologically confirmed advanced stage tumor; signs of cancer-related anorexia/cachexia syndrome present Prue et al. [15] Gynecologic cancers Newly diagnosed with no treatment except surgery Prospective phase II clinical trial to test the safety and effectiveness of an intervention with the COX-2 inhibitor celecoxib on key variables of cachexia (including fatigue) in patients with advanced cancer of different disease sites Phase III randomized trail to establish the most effective and safest treatment to improve key primary endpoints of CACS: increase of LBM, decrease of REE, and improvement of fatigue. Secondary endpoints also evaluated. Examine course and correlates of fatigue in gynecologic cancer patients Rief et al. [25] None (nonclinical sample) NA Test hypothesis that nocturnal secretion of inflammation markers and catecholamines would be associated with mood and stress variables Shochatetal.[27] Asymptomatic BRCA 1/2 carriers At genetic risk (asymptomatic BRCA1 2 mutation carriers and non-carriers) Taylor et al. [49] Breast cancer Completed initial treatment for breast cancer Bevans et al. [46] Allogeneic hematopoietic stellcelltransplant patients and caregivers Pre-HSCT, post-hsct, and 6 weeks postdischarge Donnelly et al. [14] Gynecologic cancer Post-surgery and in active treatment or post-treatment Investigate association between BRCA 1/2 status and sleep quality in asymptomatic women Examine relationship among cardiorespiratory fitness, physical activity, and psychosocial variables in overweight or obese breast cancer survivors Explore psychometric properties of Distress Thermometer by examining relationship with Brief Symptom Inventory - 18 and MFSI in allogeneic HSCT patients and caregivers Determine feasibility and efficacy of physical activity 40 sleep apneic patients; 8 normal patients 19 % female 49.2 (9.4) Cross-sectional Total, emotional, 24 patients 46 % female 60.6 (9.7) Longitudinal Total 332 patients 45 % female Mean (SD): Arm 1=61.5 (9.7) Arm 2=60.6 (13.5) Arm 3=62.8 (11.5) Arm 4=62.4 (11.9) Arm 5=62.4 (9.4) 65 patients; 60 noncancer 100 % female Patients 57.4 (13.9) (23 86), noncancer 55.4 (13.6) (24 86) Longitudinal Total Longitudinal Total, emotional, physical 130 individuals 43 % female 34.9 (9.6) ( ) Longitudinal Total 17 BRCA 1/2 carriers, 20 non-carriers, % female BRCA1/2 carriers: 51.4 (9.1) (42-61), non-carriers 54.5 (9.4) (45 64), 49.9 (6.8) (43 57) Cross-sectional Total 260 patients 100 % female 55 (9.4) (28 81) Cross-sectional Total 65 patients; 91 caregivers Patients: 37 % female; caregivers: 75 % female Patients 47.4 (14.3), caregivers 52.3 (13.5) Longitudinal Total, emotional, 33 patients 100 % female 53 (10.3) Total

9 Table 1 (continued) Authors Disease Position in disease/ treatment trajectory Study purpose Sample size Sex Age (mean and SD) (range) Design Scales reported in analyses and within 3 years of diagnosis Fagundes et al. [47] Breast cancer Completed treatment within the last 2 years; at least 2 months past surgery, radiotherapy or chemotherapy (whichever occurred last) Hawker et al. [17] Osteoarthritis (OA) Difficulties with movement in the last 3 months; swelling, pain, or stiffness lasting at least 6 wks Pien et al. [29] Mix of cancer types Underwent treatment but did not receive intravenous chemotherapy Rodrigue et al. [21] Kidney transplant candidates and recipients Before and after kidney transplantation Tomfohr et al. [44] Obstructive sleep apnea Have not received treatment for OSA Ancoli-Israel et al. [53] Breast cancer Prior to start of chemotherapy to last week of cycle 4 Bower et al. [54] Breast cancer At least 6 months posttreatment with persistent cancer-related fatigue Breckenridge et al. [78] Breast cancer 1 year or more post-primary treatment behavioral change intervention in managing cancer-related fatigue Evaluate relationships between fatigue and both sympathetic and parasympathetic nervous system activity in breast cancer survivors/examine relationships between fatigue and autonomic activity at rest, as well as in response to standardized laboratory stressor Examine the relationships between OA pain, disability, fatigue, and depressed mood Examine psychometric properties of Chinese version of MFSI-SF Examine fatigue and sleep quality before and after kidney transplantation Examine effects of continuous positive airway pressure (CPAP) on fatigue in patients with obstructive sleep apnea Test whether increased morning bright light, compared to dim light, results in less fatigues during chemotherapy Determine feasibility and efficacy of lyengar yoga intervention for breast cancer survivors with persistent cancer-related fatigue Examine relationship of adjuvant endocrine therapy and perceived and performance-based cognitive function in occupationally active breast cancer survivors Cordero et al. [22] None (nonclinical sample) NA Examine fatigue according to acculturation status and to evaluate the factor structure of the MFSI-SF in a Hispanic community sample Fagundes et al. [79] Breast cancer Completed treatment within the last 2 years; at least 2 months past surgery, Examine the relationships between child maltreatment and quality of life in breast cancer survivors Randomized controlled trial 109 patients 100 % female 51.7 (9.4) Longitudinal Total, emotional, 529 people completed all three assessments 107 patients; 46 noncancer 100 pre-tx patients; 100 post-tx patients 78 % female 75.4 ( ) Longitudinal Total 65 % female Patients: 53.56±11.02; range=26 83 Pre-tx patients: 38 % female; post-tx patients: 46 % female Pre-tx patients , (40 64), post-tx patients 53.1 (11.3) (42 64) 59 patients 86 % male, 14 % female Placebo: (9.04), range=39 57; Treatment: (9.69), range=38 58 Cross-sectional Total, physical (a combination of physical and general), emotional, vigor, mental Cross-sectional Total, emotional, Randomized controlled trial 39 patients 100 % female 54 (9.1) (32 70) Randomized controlled trial 31 patients 100 % female Intervention: 54.4 (5.7); control group=53.3 (4.9); range=40 65) survivors on adjuvant endocrine therapy=77; survivors not on adjuvant endocrine therapy 158 Hispanics; 176 Anglos Hispanics: 69 % female; Anglos: 62 % female 100 % female SERM/AI mn=44.9 (9.99) No SERM/AI=44.8 (8.88) Hispanics 41.2 (16.1); Anglos 58.7 (16.9) Randomized controlled trial Total Total, emotional, Vigor Cross-sectional Physical Cross-sectional Emotional, general, mental, physical, vigor 132 patients 100 % female 51.7 (9.5) Cross-sectional Total, emotional,

10 Table 1 (continued) Authors Disease Position in disease/ treatment trajectory Study purpose Sample size Sex Age (mean and SD) (range) Design Scales reported in analyses radiotherapy or chemotherapy (whichever occurred last) Liu et al. [64] Breast cancer Newly diagnosed; scheduled to receive at least 4 3 week cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy Liu et al. [52] Breast cancer Newly diagnosed; scheduled to receive at least 4 3 week cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy Examine the relationships between fatigue, objective and subjective measures of sleep, and inflammatory markers Explore longitudinal relationship between fatigue and both subjectively and objectively measured sleep Redwine et al. [35] Chronic heart failure NA Measure whether a Tai chi intervention effectively reduces somatic and/or cognitive symptoms of depression in patients with heart failure (copied directly from abstract) Ritterband et al. [55] Mix of cancer types At least 1 month since completion of active treatment Sadja et al. [20] Hypertension Not taking blood pressure medication Schmidtetal.[16] Fibromyalgia Pain duration of at least six months; current pain level of at least 30 on a visual analog scale Aynehchi et al. [80] Head and neck cancer At least 3 months post-treatment Barton et al. [62] Mix of cancer types Within 2 years of diagnosis, in active treatment or completed treatment; experiencing cancer-related fatigue Bennett et al. [81] Breast cancer Completed treatment within the last 3 years; at least 2 months post surgery, radiotherapy or chemotherapy (whichever occurred last) Evaluate effects of internet intervention designed to improve sleep of cancer survivors with insomnia Examine predictors of exercise adherence to 12-week exercise intervention Evaluate effects of focused breathing technique designed to enhance self-regulation in patients with fibromyalgia Validate Modified Brief Fatigue Inventory Evaluate efficacy and toxicity of American ginseng for cancer-related fatigue Investigate cortisol and IL-6 responses to acute laboratory stressor in former and never smokers Cormie et al. [38] Prostate cancer NR Determine the safety and efficacy of resistance exercise by prostate cancer survivors with bone metastatic disease Ganz et al. [82] Breast cancer Completed primary treatment within past 3 months Examine relationship between subjective cognitive complaints and neuropsychological 53 patients 100 % female 50.3 (9.9) Longitudinal Total 97 patients 100 % female 50.7 (9.8) Longitudinal Total, emotional, 24 patients 13 % female 67 (11.9) (43 83) Randomized controlled trial 28 patients 86 % female 56.7 (11.7) ( ) Randomized controlled trial 51 individuals 53 % female Total: (9.38); women: 49.07±8.63 range=40 58; men: 43.92±9.61 range=34 54 Randomized controlled trial Total, physical Total, emotional, Physical 20 patients 100 % female 40.8 (13.7) (27 55) Longitudinal Emotional, general, mental, physical, vigor 52 patients, 57 noncancer 55 % female 59.2 (12.8) (26 86) Cross-sectional Total 341 patients 78 % female Intervention: 55.3 (12.7), : 55.9 (11.8) 89 patients (64 never smokers, 25 former smokers) 100 % female Never smokers: 51.2 (10.2), former smokers: 52.0 (7.5) 20 patients 100 % male Patients: 73.1 (7.5); : 71.2 (6.9); range ( 57 83) Randomized controlled trial Cross-sectional Total Randomized controlled trial Total, general, emotional, mental, Total, general, emotional, mental, 189 patients 100 % female 51.8 Longitudinal Mental, physical

11 Table 1 (continued) Authors Disease Position in disease/ treatment trajectory Study purpose Sample size Sex Age (mean and SD) (range) Design Scales reported in analyses Gass and Glaros [83] Headache 6 month or longer history of recurrent headaches function, chemotherapy exposure, and menstrual status Examine association between headaches and autonomic nervous system activity Janusek et al. [66] Breast cancer Post breast surgery Determine whether childhood adversity increases vulnerability for more intense and sustained behavioral symptoms, poorer quality of life, and greater immune dysregulation Moskowitz et al. [84] Breast cancer Completed primary treatment Examine whether symptom clusters appear in employed breast cancer survivors and whether clusters are related to job stress and aerobic activity Sobel-Fox et al. [42] Mix of cancer types Completed treatment at least 3 months prior; self-reported experience of at least 3 episodes of debilitating fatigue in past month Thorndike et al. [56] Insomnia Diagnosed with insomnia; reported sleep complaints lasting at least 6 months; currently experiencing sleep difficulties and fatigue-related daytime impairment Examine relationship between unidimensional and multidimensional assessments of fatigue in cancer survivors Investigate whether Internet-delivered cognitive behavioral therapy for insomnia also reduces comorbid psychological and fatigue symptoms 21 patients; 19 healthy Patients: 90 % female; healthy : 89 % female Patients: 32.9 (11.7); healthy : 30.4 (11.2) Cross-sectional Total, emotional, 40 patients 100 % female 55.6 (9.4) Longitudinal Total 94 patients; 100 noncancer 100 % female Patients: 49.5 (8.5); : 39.9 (10.8) Cross-sectional Physical 52 patients 64 % female 57.8 (13.3) (28 84) Longitudinal Emotional, general, mental, physical, vigor 44 patients Intervention patients: 82 % female; control patients: 73 % female Total: 44.9 (11.0); intervention patients: 44.7 (10.6); control patients: 45.1 (11.7) Randomized controlled trial Total

12 Sample sizes in the identified publications ranged from a low of 10 in a double-blind crossover study [33] to determine the contribution of hyperammonemia to minimal hepatic encephalopathy development in males and a high of 529 in a longitudinal study [17] examining the relationships between osteoarthritis pain, disability, fatigue, and depressed mood. Thirty-three of the samples included in the 70 studies were 100 % female; only one study [33] included a sample that was 100 % male. Sixty-five studies reported mean age of the sample; 34 of these studies also reported age range in addition to mean age while two studies [19, 34] reported only range. The mean/median age of participants ranged from 20 to 75 years. There were few studies of older cancer patients; only six reported a mean/median age greater than 65 years of age [17, 18, 35 38]. Reliability of the MFSI-SF Internal consistency reliability Table 2 presents data related to the reliability of the MFSI-SF. Sixteen studies reported on the internal consistency reliability of the multi-item fatigue subscales. Eight of these studies [9, 10, 22, 36, 39 42]reportedon all five of the subscales: physical mean alpha=0.84 (95 % confidence interval (CI)= ), general mean alpha= 0.93 (95 % CI= ), mental mean alpha=0.87 (95 % CI= ), emotional mean alpha=0.90 (95 % CI= ), vigor mean alpha=0.86 (95 % CI= ). Two studies [36, 40] reported only a range of alpha coefficients for the subscales as a group; the lowest reported coefficient was 0.74 and the highest was Six studies [17, 21, 29, 36, 43, 44] included a Cronbach s alpha coefficient for the total fatigue score. The mean alpha coefficient for total fatigue was 0.87 (95 % CI= ) and ranged from 0.74 to One study [27] combined the MFSI-SF with the Brief Symptom Inventory and reported only that Cronbach s alpha coefficients for the combined scales ranged from 0.85 to Test-retest reliability Three studies [9, 18, 29] published data on the test-retest reliability of the MFSI-SF. The first was the Table 2 Reliability of the Multidimensional Fatigue Symptom Inventory-Short Form Authors Internal consistency reliability Test-retest reliability Stein et al. [9] General (0.96), emotional (0.93), physical (0.85), mental (0.90), vigor to 4 weeks: general (0.51), physical (0.54), emotional (0.57), mental (0.64), vigor (0.55); 6 to 8 weeks: general (0.60), physical (0.61), emotional (0.66), mental (0.70), vigor (0.64) Broeckel et al. [40] Subscale alpha range=0.81 to 0.94 (patients), =0.74 to 0.91 (noncancer ) Stein et al. [85] General (0.96), emotional (0.92), physical (0.87), mental (0.91), and vigor (0.90) de Leeuw, Studts and Carlson [41] General (0.96), emotional (0.89), physical (0.89), mental (0.90), vigor (0.88) Helgeson and Tomich [68] Patients: general (0.94), mental (0.91), physical (0.75); : general (0.94), mental (0.84), physical (0.81) Banthia et al. [39] General (0.95), emotional (0.82), physical (0.81), mental (0.84), vigor (0.79) Mead et al. [18] General: T1 (0.91), T2 (0.93) mean of 3.9 days: general (0.76) Clayton, Dudley and Musters [43] Total (0.95) Roepke et al. [36] total alpha=0.86, subscales alpha range=0.87 to 0.94 Hawker et al. [17] Total: T1 (0.74), T2 (0.85), T3 (0.89) Pien et al. [29] Physical (0.84), mental (0.84), mental (0.84), vigour (0.83), total (0.90) [mental is reported twice and emotional is not reported] Rodrigue et al. [21] Total (0.89) Tomfohr et al. [44] Total (0.84) Cordero et al. [22] Less-acculturated Hispanics: general (0.85), physical (0.83), mental (0.85), emotional (0.93), vigor (0.82); highly-acculturated Hispanics: general (0.89), physical (0.85), mental (0.84), emotional (0.92), vigor (0.86); Anglos: general (0.94), physical (0.81), mental (0.85), emotional (0.91), vigor (0.89) Sadja et al. [20] Physical (0.85) Sobel-Fox et al. [42] General (0.94), physical (0.88), mental (0.92), emotional (0.93), vigor (0.90) 2 weeks: total (0.48), physical (0.51), emotional (0.40), mental (0.66), vigour (0.46)

13 original study [9] detailing the development and psychometric evaluation of the instrument. In that study, the scales produced moderate correlations between assessments at 3- to 4-week intervals (mean=0.56 (95 % CI= )) and 6- to 8-week intervals (mean=0.64 (95 % CI= )) in a group of breast cancer patients about to start active treatment or in the posttreatment period and in a noncancer control group. The test-retest correlation, for example, was r=0.55 for vigor between the first and second administration of the MFSI-SF and 0.64 between the first and third administration. Test-retest correlations for mental fatigue were 0.64 in the first interval and 0.70 in the second. Similarly, Pien et al. [29] reported a test-retest intraclass correlation coefficient of 0.46 for vigor and 0.66 for mental fatigue over a 2-week period while Mead et al. [18]reported a test-retest correlation coefficient of 0.76 for general fatigue over a mean of 4 days. Validity of the MFSI-SF Structural validity Three studies [10, 22, 29] evaluated the factor structure of the MFSI-SF; these results reflect whether the interrelationships of the dimensions measured by the MFSI-SF correlate with the construct of interest and subscale scores. Stein et al. [10] confirmed the five-factor model of the MFSI-SF in a heterogeneous sample of cancer patients. In a study [29] examining the psychometric properties of the Chinese version of the MFSI-SF in a patient sample of mixed cancer types, factor analysis confirmed four subscales: physical, emotional, mental, and vigor. The physical and general subscales were combined to create a new physical subscale; high factor loadings and intercorrelations between subscales supported the four-factor model of the Chinese MFSI-SF. In the third study, Cordero et al. [22] evaluated the factor structure of the MFSI-SF in a Hispanic community sample. The vigor, mental, and emotional subscales were largely maintained; the general and physical subscales were not, and the study concluded that the general fatigue subscale was problematic for Hispanics. Concurrent validity Evidence bearing on the concurrent validity of the MFSI-SF was reported in seven studies identified. As shown in Table 3, MFSI-SF fatigue subscales have been shown to be positively correlated with the Profile of Mood States (POMS) fatigue subscale [10, 18, 19, 25], the Fatigue Symptom Inventory (FSI) [10, 21], and the fatigue item of the Bathy Ankylosing Spondylitis Disease Activity Index [45]. The correlation coefficients between the POMS fatigue subscale and the MFSI-SF fatigue subscales range from a low of r=0.62 with emotional fatigue to a high of 0.88 with general fatigue; both of these coefficients are from the initial psychometric study by Stein et al. [9]. Correlations between the FSI and the MFSI-SF fatigue subscales range from a low of r=0.36 between the FSI average fatigue item and emotional fatigue to a high of r=0.82 between the FSI average fatigue item and general fatigue; these coefficients are from the follow-up validation study of the MFSI-SF by Stein et al. [10]. Similarly, MFSI-SF vigor has been shown to be positively correlated with the Medical Outcomes Study 36-Item Short Form (MOS SF-36) vitality scale [9, 10]. The mean correlation between MFSI-SF vigor and the SF-36 vitality scale is 0.67 (95 % CI= ). Convergent validity Evidence bearing on the convergent validity of the MFSI-SF was reported in 26 studies (see Table 3). Correlations were reportedwiththe Distress Thermometer [46], a brief screening measure of psychological distress, and measures of depression and anxiety, including the Center for Epidemiologic Studies-Depression Scale (CES-D) [9, 17, 24, 28, 47 50], the Beck Depression Inventory-II [29], the Symptom Checklist 90-Revised- Depresssion and Anxiety Scales [15, 41], the Hospital Anxiety and Depression Scale [31], and State Trait Anxiety Inventory (STAI) [9]. Among the eight studies [9, 17, 24, 47 51] reporting associations with the CES-D, correlation coefficients ranged from 0.37 to 0.85; the mean correlation of total fatigue with the CES-D was r=0.77 (95 % CI= ). In the one study [9] reporting associations with the STAI, correlation coefficients range from 0.51 to Several studies reported correlations between MFSI-SF fatigue subscales and measures of sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) [21, 27, 36, 48, 50, 52, 53]. Among the seven studies reporting associations with the PSQI, correlation coefficients range from 0.15 to The mean correlation of MFSI-SF total fatigue with PSQI total was 0.45 (95 % CI= ). Divergent validity Evidence bearing on the divergent validity of the MFSI-SF was reported in 16 studies (see Table 3). Most notably, negative correlations were reported between the MFSI-SF fatigue subscales and the MOS SF-36 scales [9, 18, 29, 31] and between the MFSI-SF vigor subscale and the Symptom Checklist-90-Revised [41]. Discriminative validity In Table 4, we present discriminative validity data for the MFSI-SF from 30 studies. To briefly summarize the instrument s ability to discriminate between groups, we focus herein on the 15 studies comparing a patient group with a specific medical condition to a nonpatient control group on the MFSI-SF. The mean effect size across the 15 studies on each of the subscales is as follows: physical mean d=0.73 (95 % CI= ), general mean d=0.78 (95 % CI= ), mental mean d=0.54 (95 % CI= ), emotional mean d=.53 (95 % CI= ), vigor mean d=.76 (95 % CI= ). Consistent with Cohen s categorization of effect sizes [11], the magnitude of these effects