Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

A pilot trial of RNS60 in amyotrophic lateral sclerosis.

INTRODUCTION: RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclinical models. RNS60 is administered by weekly intravenous infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients. METHODS: The planned treatment duration was 23 weeks and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomography (PET) imaging and plasma biomarkers of inflammation. RESULTS: Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 weeks of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers. DISCUSSION: Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression. Muscle Nerve 59:303-308, 2019.

Fixed dynamometry is more sensitive than vital capacity or ALS rating scale.

INTRODUCTION: Improved outcome measures are essential to efficiently screen the growing number of potential amyotrophic lateral sclerosis (ALS) therapies. METHODS: This longitudinal study of 100 (70 male) participants with ALS compared Accurate Test of Limb Isometric Strength (ATLIS), using a fixed, wireless load cell, with ALS Functional Rating Scale-Revised (ALSFRS-R) and vital capacity (VC). RESULTS: Participants enrolled at 5 U.S. sites. Data were analyzed from 66 participants with complete ATLIS, ALSFRS-R, and VC data over at least 3 visits. Change in ATLIS was less variable both within- and among-person than change in ALSFRS-R or VC. Additionally, participants who had normal ALSFRS-R arm and leg function averaged 12 to 32% below expected strength values measured by ATLIS. CONCLUSIONS: ATLIS was more sensitive to change than ALSFRS-R or VC and could decrease sample size requirements by approximately one-third. The ability of ATLIS to detect prefunctional change has potential value in early trials. Muscle Nerve 56: 710-715, 2017.

Developing normalized strength scores for neuromuscular research.

INTRODUCTION: The Accurate Test of Limb Isometric Strength (ATLIS) device can reliably measure the strength of 12 muscle groups using a fixed load cell. The purpose of this study was to analyze ATLIS data from healthy adults to calculate an individual's predicted strength scores. METHODS: ATLIS data were collected from 432 healthy adults. Linear regression models were developed to predict each muscle group's strength. The R-squared statistic assessed variability accounted for by the models. RESULTS: Simple main effects models stratified by gender were used to establish regression equations for each muscle using factors of age, weight, and height. CONCLUSIONS: Normalizing raw strength scores controls for biometric factors, thus enabling meaningful comparisons between subjects and allowing each muscle to contribute equally to a summary score. Normalized scores are easily interpreted for broad clinical uses, and derived summary scores establish individuals' disease progression rates using a common scale, allowing for more efficient clinical trials.

Validation of a new strength measurement device for amyotrophic lateral sclerosis clinical trials.

INTRODUCTION: Strength measures with reduced variability and higher sensitivity could improve efficiency in clinical trials of amyotrophic lateral sclerosis (ALS). The Accurate Test of Limb Isometric Strength (ATLIS) was developed to precisely and conveniently measure force in 12 muscle groups. In this study we evaluate the reliability and validity of the ATLIS testing protocol. METHODS: Twenty healthy adults and 10 patients with ALS were tested twice by the same or by different evaluators to determine test-retest and interrater reliability. Twenty healthy adults were examined using ATLIS and a well-validated strength testing protocol (TQNE) to assess criterion-based validity. RESULTS: Mean absolute variation between tests was 8.6%, and intraclass correlation coefficients for each muscle group were high (range 0.82-0.99). The Pearson correlation coefficient of mean ATLIS and TQNE scores was 0.90. A subject survey demonstrated high user acceptance of ATLIS. CONCLUSIONS: ATLIS is convenient for patients and evaluators, produces precise strength measurements, and is easily moved between examining rooms.

Phase 2 study of sodium phenylbutyrate in ALS.

The objective of the study was to establish the safety and pharmacodynamics of escalating dosages of sodium phenylbutyrate (NaPB) in participants with ALS. Transcription dysregulation may play a role in the pathogenesis of ALS. Sodium phenylbutyrate, a histone deacetylase inhibitor, improves transcription and post-transcriptional pathways, promoting cell survival in a mouse model of motor neuron disease. Forty research participants at eight sites enrolled in an open-label study. Study medication was increased from 9 to 21 g/day. The primary outcome measure was tolerability. Secondary outcome measures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage. Twenty-six participants completed the 20-week treatment phase. NaPB was safe and tolerable. No study deaths or clinically relevant laboratory changes occurred with NaPB treatment. Histone acetylation was decreased by approximately 50% in blood buffy-coat specimens at screening and was significantly increased after NaPB administration. Blood levels of NaPB and the primary metabolite, phenylacetate, increased with dosage. While the majority of subjects tolerated higher dosages of NaPB, the lowest dose (9 g/day), was therapeutically efficient in improving histone acetylation levels.

Patients with ALS show highly correlated progression rates in left and right limb muscles.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression. METHODS: A large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb. RESULTS: This report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent. CONCLUSIONS: First, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials.

Depression in orthopaedic trauma patients. Prevalence and severity.

BACKGROUND: There is a known connection between physical injury and disability and emotional distress. Several investigators have shown a relationship between trauma, depression, and poor outcomes. The literature on trauma and depression is limited with regard to clarifying the relationship between the degree of injury and depression and the relationship between physical function of patients with less severe injuries and depression. METHODS: One hundred and sixty-one patients who presented to our orthopaedic trauma services were enrolled in the study and interviewed. We obtained information about patient demographics and administered several self-reported outcome measures: the Beck Depression Inventory (BDI), the Short Musculoskeletal Function Assessment (SMFA), and the Physical Function-10 (PF-10) subset of the Short Form-36 (SF-36). We documented the nature and severity of the injury or injuries and calculated correlations between the outcome measures and the BDI. Injury-specific factors such as the AO Fracture Classification, the Abbreviated Injury Scale (AIS), the Injury Severity Score (ISS), and the Gustilo and Anderson grade of open fractures were also examined. RESULTS: Fifty-five percent of the patients had minimal depression, as measured with the BDI; 28% had moderate depression; 13% had moderate-to-severe depression; and 3.7% had severe depression. When the somatic elements of the BDI were removed, the prevalence of moderate, moderate-to-severe, or severe depression was 26%. The SMFA scores had a strong negative correlation with the BDI (-0.75; p < 0.001). Of the injury-specific factors, only open factures were found to have an impact on the presence of depression, with an odds ratio of 4.58 (95% confidence ratio, 1.57 to 12.35). CONCLUSIONS: The prevalence of clinically relevant depression approached 45% in a diverse cohort of orthopaedic trauma patients. Global disability is strongly correlated with depression. The presence of an open fracture may also increase the risk of depression. LEVEL OF EVIDENCE: Prognostic Level II.

An assessment tool translation study.

Policymakers hoped to substitute a new, multi-purpose, functional assessment instrument, the minimum data set post-acute care (MDS-PAC), into the planned prospective payment system (PPS) for inpatient rehabilitation hospitals. PPS design requires a large database linking treatment costs with measures of the need for care, so the PPS was designed using the functional independence measure (FIM) database linked to Medicare hospital claims. An accurate translation from the MDS-PAC items to FIM--like items was needed to ensure payment equity under the substitution. This article describes the translation efforts and some of the problems that led policymakers to abandon the effort.

Computer adaptive testing: a strategy for monitoring stroke rehabilitation across settings.

Current functional assessment instruments in stroke rehabilitation are often setting-specific and lack precision, breadth, and/or feasibility. Computer adaptive testing (CAT) offers a promising potential solution by providing a quick, yet precise, measure of function that can be used across a broad range of patient abilities and in multiple settings. CAT technology yields a precise score by selecting very few relevant items from a large and diverse item pool based on each individual's responses. We demonstrate the potential usefulness of a CAT assessment model with a cross-sectional sample of persons with stroke from multiple rehabilitation settings.

An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study.

BACKGROUND: Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis. METHODS: In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 mg, 1·50 mg, 3·00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222. FINDINGS: Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated. INTERPRETATION: This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders. FUNDING: The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.

Measuring physical function in patients with complex medical and postsurgical conditions: a computer adaptive approach.

OBJECTIVE: To examine whether the range of disability in the medically complex and postsurgical populations receiving rehabilitation is adequately sampled by the new Activity Measure--Post-Acute Care (AM-PAC), and to assess whether computer adaptive testing (CAT) can derive valid patient scores using fewer questions. DESIGN: Observational study of 158 subjects (mean age 67.2 yrs) receiving skilled rehabilitation services in inpatient (acute rehabilitation hospitals, skilled nursing facility units) and community (home health services, outpatient departments) settings for recent-onset or worsening disability from medical (excluding neurological) and surgical (excluding orthopedic) conditions. Measures were interviewer-administered activity questions (all patients) and physical functioning portion of the SF-36 (outpatients) and standardized chart items (11 Functional Independence Measure (FIM), 19 Standardized Outcome and Assessment Information Set (OASIS) items, and 22 Minimum Data Set (MDS) items). Rasch modeling analyzed all data and the relationship between person ability estimates and average item difficulty. CAT assessed the ability to derive accurate patient scores using a sample of questions. RESULTS: The 163-item activity item pool covered the range of physical movement and personal and instrumental activities. CAT analysis showed comparable scores between estimates using 10 items or the total item pool. CONCLUSION: The AM-PAC can assess a broad range of function in patients with complex medical illness. CAT achieves valid patient scores using fewer questions.

Is patient-reported function reliable for monitoring postacute outcomes?

OBJECTIVE: A major challenge in the development of a comprehensive measurement system to evaluate effectiveness across a broad range of postacute care settings is the stability and consistency of outcomes measures across respondents and settings. The objective of this study was to investigate the test-retest and subject-proxy reliability of activity scores for use in a new postacute care outcome instrument using an interview format across different care settings. DESIGN: Twenty-five subjects were randomly selected from a larger study of 485 individuals and were interviewed on two occasions within 1 to 4 days to assess self-reported test-retest reliability of summary scores of the Activity Measure-Post-Acute Care item pool. Proxy reliability was tested by interviewing the primary physical or occupational therapist or family member using an identical questionnaire in addition to the subject in 45 patients. RESULTS: Test-retest and subject-proxy reliability was acceptable for the three domains of the activity construct: physical and movement, personal and instrumental, and applied cognition with intraclass correlation coefficients of the summary scores of each of the three domains ranging between 0.91 and 0.97 for test-retest and 0.68 and 0.90 for subject-proxy. CONCLUSIONS: Reliability is adequate to justify use of these activity scales across respondents and settings.

Score comparability of short forms and computerized adaptive testing: Simulation study with the activity measure for post-acute care.

OBJECTIVE: To compare simulated short-form and computerized adaptive testing (CAT) scores to scores obtained from complete item sets for each of the 3 domains of the Activity Measure for Post-Acute Care (AM-PAC). DESIGN: Prospective study. SETTING: Six postacute health care networks in the greater Boston metropolitan area, including inpatient acute rehabilitation, transitional care units, home care, and outpatient services. PARTICIPANTS: A convenience sample of 485 adult volunteers who were receiving skilled rehabilitation services. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Inpatient and community-based short forms and CAT applications were developed for each of 3 activity domains (physical & mobility, personal care & instrumental, applied cognition) using item pools constructed from new items and items from existing postacute care instruments. RESULTS: Simulated CAT scores correlated highly with score estimates from the total item pool in each domain (4- and 6-item CAT r range,.90-.95; 10-item CAT r range,.96-.98). Scores on the 10-item short forms constructed for inpatient and community settings also provided good estimates of the AM-PAC item pool scores for the physical & movement and personal care & instrumental domains, but were less consistent in the applied cognition domain. Confidence intervals around individual scores were greater in the short forms than for the CATs. CONCLUSIONS: Accurate scoring estimates for AM-PAC domains can be obtained with either the setting-specific short forms or the CATs. The strong relationship between CAT and item pool scores can be attributed to the CAT's ability to select specific items to match individual responses. The CAT may have additional advantages over short forms in practicality, efficiency, and the potential for providing more precise scoring estimates for individuals.

Short-form activity measure for post-acute care.

OBJECTIVE: To develop a comprehensive set of short forms using item response theory (IRT) and item pooling procedures for the purpose of monitoring postacute care functional recovery. DESIGN: Prospective study. SETTING: Six postacute health care networks in the greater Boston area, including inpatient acute rehabilitation, transitional care units, home care, and outpatient services. PARTICIPANTS: A convenience sample of 485 adult volunteers who were currently receiving skilled rehabilitation services. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We developed a set of 6 short forms across 3 activity domains from new items and items from existing postacute care instruments. RESULTS: Inpatient- and community-based short forms were developed for each of 3 activity domains: physical & movement, applied cognition, and personal care & instrumental. Items were selected for inclusion on the short forms to maximize content coverage and information value of items across the range of content and to minimize ceiling and floor effects. We were able to match the distribution of sample scores with very good item precision for 1 of the constructs (physical & movement); the other 2 domains (personal care & instrumental, applied cognition) were more challenging because of the variability in patient recovery and ceiling effects. CONCLUSIONS: ITR methods and item pooling procedures were valuable in developing paired sets of short-form instruments for inpatient and community rehabilitation that provided estimates of functioning along a common metric for use across postacute care settings.

Evaluating the planned substitution of the minimum data set-post acute care for use in the rehabilitation hospital prospective payment system.

OBJECTIVE: The objective of this study was to evaluate the payment implications of substituting the Minimum Data Set-Post Acute Care (MDS-PAC) for the FIM trade mark instrument for use in the planned prospective payment system (PPS) for inpatient rehabilitation hospitals. FIM trade mark is a trademark of the Uniform Data System for Medical Rehabilitation, a division of UB Foundation Activites, Inc. RESEARCH DESIGN: We used a prospective cross-sectional design using consecutive sampling. SUBJECTS: We studied all Medicare admissions with stays of 3 days or more over a 2-month period to 50 inpatient rehabilitation hospitals in 22 states. MEASUREMENTS AND METHODS: Each participating institution completed both the FIM and the MDS-PAC assessments on all participants. Items from the MDS-PAC were combined and translated to create "FIM-like" items. We assessed agreement of classification into prospective payment cells using FIM assessment data and also using MDS-PAC data. Statistical adjustments were applied to improve the level of agreement. RESULTS: The mean differences between the FIM motor and cognitive scales and their MDS-PAC translations were 2.4 (mean = 45) and 0.0 (mean = 28), respectively, with scale correlations of.85 and.84. Weighted kappas on individual items ranged from.32 to.64. There were substantial hospital-specific differences in scoring. Payment cell classification using FIM data agreed with that using MDS-PAC data only 56% of the time. Twenty percent of the facilities experienced revenue shifts larger than 10%. CONCLUSION: Despite better item-level agreement than previously observed, poor payment cell agreement and substantial revenue shifts indicated that the MDS-PAC should not be substituted for the FIM trade mark instrument in the rehabilitation hospital PPS.

Development of an applied cognition scale to measure rehabilitation outcomes.

OBJECTIVE: To examine the structure and content coverage of an item pool of new items based on the Activity categories from the International Classification of Functioning, Disability and Health and items from existing instruments to measure the applied cognition dimension of function. DESIGN: Prospective study. SETTING: Four postacute care rehabilitation settings (inpatient, transitional care, home care, outpatient) in an urban-suburban area of northeast United States. PARTICIPANTS: Convenience sample of 477 patients (mean age, 62.7 y) receiving rehabilitation services for neurologic, orthopedic, or complex medical conditions. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were administered applied cognition items from the new Activity Measure for Post-Acute Care, the Medical Outcomes Study 8-Item Short-Form Health Survey, and an additional setting-specific measure: the FIM instrument (inpatient rehabilitation); the Minimum Data Set (skilled nursing facility); the Minimum Data Set-Post Acute Care (postacute settings); or the Outcome Assessment and Information Set (home care). Rasch (partial-credit model) analyses were conducted to examine item fit, item coverage, scale unidimensionality, and category difficulty estimates. RESULTS: The majority of items (46/59) could be located along a single continuum. Relatively few people were performing at the lower end of the difficulty scale, and about 25% were at ceiling. CONCLUSIONS: The proposed definition of applied cognition dimension provides a useful guide for item development to measure this dimension. Further work is needed to determine how best to measure function in this domain for people at the upper and lower ends of the continuum.

Activity outcome measurement for postacute care.

BACKGROUND: Efforts to evaluate the effectiveness of a broad range of postacute care services have been hindered by the lack of conceptually sound and comprehensive measures of outcomes. It is critical to determine a common underlying structure before employing current methods of item equating across outcome instruments for future item banking and computer-adaptive testing applications. OBJECTIVE: To investigate the factor structure, reliability, and scale properties of items underlying the Activity domains of the International Classification of Functioning, Disability and Health (ICF) for use in postacute care outcome measurement. METHODS: We developed a 41-item Activity Measure for Postacute Care (AM-PAC) that assessed an individual's execution of discrete daily tasks in his or her own environment across major content domains as defined by the ICF. We evaluated the reliability and discriminant validity of the prototype AM-PAC in 477 individuals in active rehabilitation programs across 4 rehabilitation settings using factor analyses, tests of item scaling, internal consistency reliability analyses, Rasch item response theory modeling, residual component analysis, and modified parallel analysis. RESULTS: Results from an initial exploratory factor analysis produced 3 distinct, interpretable factors that accounted for 72% of the variance: Applied Cognition (44%), Personal Care & Instrumental Activities (19%), and Physical & Movement Activities (9%); these 3 activity factors were verified by a confirmatory factor analysis. Scaling assumptions were met for each factor in the total sample and across diagnostic groups. Internal consistency reliability was high for the total sample (Cronbach alpha = 0.92 to 0.94), and for specific diagnostic groups (Cronbach alpha = 0.90 to 0.95). Rasch scaling, residual factor, differential item functioning, and modified parallel analyses supported the unidimensionality and goodness of fit of each unique activity domain. CONCLUSIONS: This 3-factor model of the AM-PAC can form the conceptual basis for common-item equating and computer-adaptive applications, leading to a comprehensive system of outcome instruments for postacute care settings.

Refining the conceptual basis for rehabilitation outcome measurement: personal care and instrumental activities domain.

BACKGROUND: Rehabilitation outcome measures routinely include content on performance of daily activities; however, the conceptual basis for item selection is rarely specified. These instruments differ significantly in format, number, and specificity of daily activity items and in the measurement dimensions and type of scale used to specify levels of performance. We propose that a requirement for upper limb and hand skills underlies many activities of daily living (ADL) and instrumental activities of daily living (IADL) items in current instruments, and that items selected based on this definition can be placed along a single functional continuum. OBJECTIVE: To examine the dimensional structure and content coverage of a Personal Care and Instrumental Activities item set and to examine the comparability of items from existing instruments and a set of new items as measures of this domain. METHODS: Participants (N = 477) from 3 different disability groups and 4 settings representing the continuum of postacute rehabilitation care were administered the newly developed Activity Measure for Post-Acute Care (AM-PAC), the SF-8, and an additional setting-specific measure: FIM (in-patient rehabilitation); MDS (skilled nursing facility); MDS-PAC (postacute settings); OASIS (home care); or PF-10 (outpatient clinic). Rasch (partial-credit model) analyses were conducted on a set of 62 items covering the Personal Care and Instrumental domain to examine item fit, item functioning, and category difficulty estimates and unidimensionality. RESULTS: After removing 6 misfitting items, the remaining 56 items fit acceptably along the hypothesized continuum. Analyses yielded different difficulty estimates for the maximum score (eg, "Independent performance") for items with comparable content from different instruments. Items showed little differential item functioning across age, diagnosis, or severity groups, and 92% of the participants fit the model. CONCLUSIONS: ADL and IADL items from existing rehabilitation outcomes instruments that depend on skilled upper limb and hand use can be located along a single continuum, along with the new personal care and instrumental items of the AM-PAC addressing gaps in content. Results support the validity of the proposed definition of the Personal Care and Instrumental Activities dimension of function as a guide for future development of rehabilitation outcome instruments, such as linked, setting-specific short forms and computerized adaptive testing approaches.