Development and psychometric performance of the schizophrenia objective functioning instrument: An interviewer administered measure of function

Schizophrenia Research 107 (2009) 275–285

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Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s

Development and psychometric performance of the schizophrenia objective functioning instrument: An interviewer administered measure of function Leah Kleinman a,⁎, Jeffrey Lieberman b, Sanjay Dube c, Richard Mohs c, Yang Zhao c, Bruce Kinon c, William Carpenter d, Philip D. Harvey e, Michael F. Green f, Richard S.E. Keefe g, Lori Frank h, Lee Bowman c, Dennis A. Revicki h a

United BioSource Corporation, Seattle, WA, United States Columbia University, New York, NY, United States c Eli Lilly & Co., Indianapolis, IN, United States d Maryland Psychiatric Research Center, University of Maryland School of Medicine, and the VISN 5 MIRECC, Baltimore, MD, United States e Mt. Sinai School of Medicine, New York, NY, United States f UCLA Semel Institute for Neuroscience and Human Behavior and VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States g Duke University Medical Center, Durham, NC, United States h United BioSource Corporation, Bethesda, MD, United States b

a r t i c l e

i n f o

Article history: Received 20 May 2008 Received in revised form 30 September 2008 Accepted 2 October 2008 Available online 14 November 2008 Keywords: Functioning Outcomes assessment Schizophrenia Cognitive impairment Reliability Validity

a b s t r a c t Existing measures for functional assessment do not adequately address the relationship between cognitive impairment and function. The Schizophrenia Outcomes Functioning Interview (SOFI) was developed to measure community functioning related to cognitive impairment and psychopathology. Following review of existing measures and discussion with experts, caregivers, and patients, content was generated for four domains: 1) living situation; 2) IADLs; 3) productive activities; and 4) social functioning. The final SOFI was constructed with items informing domain scores, and an interviewer-completed global rating for each domain. Psychometric characteristics of the SOFI were evaluated in a sample of 104 community residing patients with schizophrenia and their informants. Test–retest reliability was evaluated in a subsample of patient–informant dyads using ICC; all values were N 0.70 for both patient-interviews (SOFI-P) and informant-interviews (SOFI-I). Inter-rater reliability ICCs ranged from 0.50 to 0.79 on a different sub-sample. The SOFI demonstrated adequate construct validity based on correlations with the PSP (range 0.58 to 0.76; p b 0.0001) and the QLS (p b 0.001). Some correlations between SOFI and PETiT scores were low to moderate (p b 0.05). Discriminant validity was supported based on SOFI score comparisons for patient groups based on PANSS and BACS scores (p b 0.05); SOFI scores differed between borderline and moderately ill patients as measured by the CGI-S (p b 0.05). The SOFI expands on existing measures and more comprehensively captures functioning of patients in the real world than other performance-based (proxy) measures. The SOFI has good evidence supporting reliability and construct validity, and may be a useful measure of functional outcomes in schizophrenia. © 2008 Elsevier B.V. All rights reserved.

1. Introduction ⁎ Corresponding author. United BioSource Corporation 1417 4th Avenue, Suite 510, Seattle, WA 98101, United States. Tel.: +1 206 448 7877; fax: +1 206 448 4644. E-mail address: [email protected] (L. Kleinman). 0920-9964/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2008.10.002

Schizophrenia is a devastating illness with a variable and chronic course. It is one of the top five causes of disability among young adults in developed countries (Murray and Lopez, 1996) and is associated with substantial impairments

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in functional outcomes, including social and occupational functioning, independent living, and the ability to perform activities of daily living (Bryson and Bell, 2003; Gaite et al., 2002; Green et al., 2000; Harvey et al., 2004; Kasckow et al., 2001; Pinikahana et al., 2002). A range of functional outcome measures have been used in previous studies in schizophrenia, measuring social and occupational function (Bell and Bryson, 2001; Bryson et al., 1998; McGurk et al., 2003), activities of daily living, and ability to live independently (Buchanan et al., 2005; Matza et al., 2006). Despite the importance of assessing functional outcomes of treatment of cognitive impairment, the link between cognition and functioning is not a focus of existing measures. The National Institute of Mental Health — Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) concluded that there was insufficient information on available functional outcome measures to recommend any as co-primary endpoints in clinical trials of cognition-enhancing drugs (Buchanan et al., 2005). The NIMH-sponsored Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) program uses both an interview-based measure, the Schizophrenia Cognition Rating Scale (SCoRS) and a performance based measure, the University of California Performance-Based Skills Assessment, as co-primary measures of cognition and functional capacity, respectively. However, performance based functional outcome measures may not fully capture the patient's usual activities and level of functioning in the community, despite their substantial correlation with cognitive performance measures. Additionally, scales that measure community function such as the Independent Living skills (ILS) were developed for making treatment related decisions by clinicians (Loeb, 1996) and not to evaluate the relationship between cognitive impairment and function. Research indicates that cognitive impairments, common among schizophrenics, have implications for multiple domains of functional status including independent living, social functioning, employment status, occupational limitations, and instrumental activities of daily living (Addington and Addington, 2000; Bell and Bryson, 2001; Bryson and Bell, 2003; Bryson et al., 1998; Green et al., 2000, 2004; Kasckow et al., 2001; McGurk et al., 2003; Palmer et al., 2002). Most functional outcome measures used in longitudinal studies focus on just one or two functioning domains (Matza et al., 2006). For example, the Assessment of Interpersonal Problem Solving Skills (Donahoe et al., 1990) and the Social Behavior Schedule (Wykes and Sturt, 1986) only assess social functioning. Few existing functional outcome measures have adequate evidence supporting psychometric performance (e.g., reliability, validity) although some demonstrate floor or ceiling effects, making them less useful for longitudinal and intervention studies (Buchanan et al., 2005; Matza et al., 2006). Unlike other diseases in which loss of ability to perform activities is important to measure, in schizophrenia both ability loss and appropriateness of efforts are relevant. Measures dependent on patient self-report may be unreliable in the case of many schizophrenic patients (Bowie et al., 2007; Fitzgerald et al., 2001; Keefe et al., 2006; Khatri et al., 2001). Therefore, new functional outcome measures are needed with assessment based on more observable behavior, sound psychometric characteristics, comprehensive coverage of

important domains, and which are sensitive to changes in functional impairment in patients with schizophrenia. Currently, the existing functional outcome measures do not comprehensively cover multiple relevant domains and have insufficient evidence supporting their measurement properties for clinical studies. The objective of this current instrument development effort was to develop a functional outcome measure that could be used in clinical trials and other clinical studies evaluating interventions for cognitive impairment and psychopathology with schizophrenia. 2. Methods 2.1. Development of the SOFI The SOFI was developed to measure changes in functional outcomes due to patient psychopathology and cognitive impairment. The development process was iterative, beginning with a literature review and consultation with experts in the field. Clinical experts were selected based on their experience and involvement in research on clinical and functional outcomes in schizophrenia (including WC and MFG; others can be found in acknowledgments). Fig.1 provides a detailed flowchart of the process. From an initial meeting of experts four domains emerged as most relevant to a functional outcome measure in schizophrenia: 1) living situation (stability, structure/supervision, independence); 2) instrumental activities of daily living (financial management, transportation, medication, treatment, housework/childcare, self-care, shopping, food/cooking, planning and leisure activities); 3) productive activities (work, other vocational oriented activities, treatment-related activities, education, homemaking/childcare); and 4) social functioning (social activity and social support). Existing measures were reviewed to identify relevant items (Fig. 1). The 362 identified items were grouped into the four domain areas and reviewed for content. Items were reviewed to determine whether they fit the SOFI conceptual framework, described potentially observable behavior or activities, and were clearly worded. This item review indicated that some additional item generation was necessary to achieve the measurement goals. A total of 122 additional items were constructed covering more observable everyday, productive and social activities usually performed by patients with schizophrenia. Clinical expert consensus was that format of the new measure should require a relatively simple interview procedure and brief instructions to permit a trained rater to score each domain based on all available data, and that the instrument should be based on observable behavior. Two versions were created, one for administration to the patient (SOFI-P) and one for administration to a caregiver informant (SOFI-I). Item content was drafted based on the 4 identified domains. Content validity of the initial draft SOFI was rated by 8 independent international schizophrenia clinical researchers based on their evaluation of item/content relevancy, potential sensitivity to meaningful change, and clarity of wording (Wynd et al., 2003). These additional clinical experts were selected based on their clinical and research experience in schizophrenia. Revisions were made to the SOFI based on their comments and recommendations. Discussions about instrument revisions continued until there was agreement among the developers.

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Fig. 1. SOFI development process. ⁎Included Independent Living Scale (ILS) (Ashley et al., 2001), LQLP (Oliver et al., 1997), Social Functioning Scale (SFS) (Birchwood et al., 1990), WHO DAS-S (Janca et al., 1996), WHO-DAS-II (Chisolm et al., 2005), WHOQOL (Study protocol for the World Health Organization project to develop a Quality of Life assessment instrument (WHOQOL), 1993), Alzheimer Disease Cooperative Study — Activities of Daily Living (ADCS-ADL) (Galasko et al., 1997), Schizophrenia Outcome Assessment Project (SOAP), Quality of Well-Being Scale (QWB) (Kaplan et al., 1984), Social Adjustment Scale (SAS) (Barrabee et al., 1955), Sickness Impact Profile (Bergner et al., 1981), Schizophrenia Care and Assessment Program Health Questionnaire (SCAP) (Lehman et al., 2003).

Two focus groups were conducted using patients and informants recruited from a clinical site, one with 4 patients and one with 4 informants. Patients were primarily black (75%) with a mean age of 45.8 years. Patients discussed their living situation, aspects of functioning, and social and productive activities. Of the 4 informants, only one was a paid caregiver while the remaining 3 were family members. Fifty percent of

the informants were white and the remaining 50% were black with a mean age of 52 years. Informants reviewed the SOFI for the relevance of the domains and probes. Relevance was confirmed, and language used by patients and caregivers was incorporated into the next draft. We completed multiple iterations of review and revisions by the developers and clinical experts to develop the final SOFI instrument.

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2.2. Psychometric evaluation of the SOFI Psychometric performance of the SOFI-P and SOFI-I was evaluated in a cross-sectional study conducted at 9 US academic and private clinical psychiatric sites; all sites had participated in the National Institute of Mental Healthsponsored Clinical Antipsychotic Trials of Intervention Effectiveness (Lieberman et al., 2005). Institutional Review Board approval was obtained, training was conducted at each site and patients and caregivers signed written consent forms. Patients were required to have a diagnosis of either schizophrenia or schizoaffective disorder, reside in the community, and be N 18 years of age, with an informant willing to participate. Patients were excluded if, in the opinion of the investigator, they had a clinically relevant condition that would interfere with completing the study (e.g., visual problems, any cognitive impairment such as Alzheimer's Disease or acute mental illness beyond what was required for study participation), or participation in a research study that included the use of investigational medications). Patients with concomitant substance abuse problems were eligible. To ensure recruitment across a wide spectrum of functioning, sites were directed to recruit roughly one third of their sample from one of each of three different types of community living situation: unrestricted (e.g., community dwelling with minimal or no formal supervision), semirestricted (e.g., group home with minimal staff supervision or community dwelling with regular day program attendance), and restricted (group home with 24-hour staff supervision). Timely recruitment was prioritized over formal stratification. Informants were required to be N 21 years of age, currently providing care, as either a formal paid caregiver (e.g., case manager, staff in group home) or an informal caregiver (e.g., family or friend) to the patient for at least one month prior to the study. For informal caregivers, self-identified care provision was considered sufficient, and they needed to directly observe the patient at least twice per month. Informants were ineligible if they had any medical condition or impairment that would interfere with the completion of an interview and forms. The SOFI-P and the SOFI-I interviews were completed prior to administration of the other study measures; the patient interview was always conducted first. Following completion of the SOFI interview with the patient, clinicians rated patients' current symptoms using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) and the Clinical Global Impressions-Severity (CGI-S) (Guy, 1976). Patients' cognitive abilities were rated using the Brief Assessment of Cognition in Schizophrenia (BACS) (Keefe et al., 2004). At some sites, a different clinician administered the SOFI and other study measures, but this was not consistent across sites. Interviewers were instructed to use any source of information about the patient when administering and scoring both the SOFI-P and the SOFI-I in concert with the intended use of the SOFI in clinical practice. Twenty-five percent of the patient–informant dyads were randomly selected to participate in a test–retest visit between 1 and 2 weeks after initial interview to complete a second interview. An additional independent 25% of the sample was randomly selected to complete an inter-rater reliability

condition — each patient and informant in this group was administered the SOFI twice in one day by two different clinical raters. Each site was specified to provide 25% of their recruited patients for each type of reliability assessment. 2.3. Clinical measures Clinical information regarding diagnosis, medication regimen, recent hospitalizations, and length of time since initial diagnosis of schizophrenia was obtained from charts. In addition, a clinician completed the CGI-S (Guy, 1976), PANSS (Kay et al., 1987), and the BACS (Keefe et al., 2004). The BACS (Keefe et al., 2004) assesses cognitive function (including verbal memory and learning, working memory, motor function, verbal fluency and executive fluency) in patients with schizophrenia via six tests (verbal memory, digit sequencing, token motor, verbal fluency, tower of London and symbol coding). The composite score is generated by averaging the six scores and calculating a z-score of the composite (Keefe et al., 2004). 2.4. Functional outcome measures — patient and informant reported 2.4.1. SOFI The SOFI is interviewer-administered and content is organized into four domains: living situation, instrumental

Table 1 SOFI content Domain

Sub-domains

Sample item probes

Living situation

• Current residence • Ability to access residence without supervision or monitoring • Autonomy in scheduling

• Does the patient have unsupervised access to his/her home or room? • Does the patient decide when to awaken, when to eat? • Can the patient come and go as he/she wishes?

IADL

• Ability to complete selfcare • Psychiatric treatment adherence • Money management skills

• Does the patient need assistance with shopping? • Does the patient seek out medical care on his/her own or is someone else responsible for overseeing his/her treatment? • How independently can the patient travel? • Does the patient organize him/ herself properly knowing what she/he will need for the day?

• Planning skills • Transportation • Leisure activities

Productive activities

• Working • Volunteering • Parenting • Vocational training • Education • Attendance at a day treatment program

Social • Appropriateness of social functioning interaction • Initiation of activities

• Does the patient have a job coach at the job? • Does the patient need help staying on-task or focusing on the tasks at hand? • What other productive activities does the patient do? • Can the patient depend on his/ her family? • Does the patient maintain an appropriate social distance? • What kind of social network does the patient have?

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activities of daily living, productive activities and social function (see Table 1 and Appendix). Each domain is measured by closed-ended items, completed after a series of probe questions, and a final global rating completed by the interviewer. The closed-ended items address amount of supervision or assistance required and mastery of the area (e.g., autonomy, degree of assistance required) and are rated on a 4, 6 or 7 point scale. The global rating for each domain ranges from 1 (poor functioning) to 100 (excellent functioning), with anchors provided for each 10 point interval. For example, for the IADL global rating level of 1–10, the anchor reads, “patient needs constant assistance with IADLs: needs constant assistance with medial treatment and does not leave residence or engage in leisure activities.” In addition to the four domain scores, an overall global score is calculated by taking the mean of the four domain global scores. 2.4.2. Quality of Life Scale (QLS) The QLS was developed to address deficit symptoms (Heinrichs et al., 1984). There are four subscales: intrapsychic foundations; interpersonal relations; instrumental role; common objects and activities. The QLS has been used extensively in schizophrenia and provides conceptual overlap with some of the SOFI domains and was used to assess construct validity. 2.4.3. Personal evaluation of transitions in treatment The PETiT was designed to measure aspects of quality of life in individuals currently on antipsychotic drug therapy (Voruganti and Awad, 2002). The PETiT includes both a quality of life and a medication subscale. Content overlaps in part with the SOFI, and specific items address key cognitiverelated functioning. The PETiT was used to assess construct validity. 2.4.4. Personal and Social Performance Scale (PSP) The PSP is interviewer-administered to the informant who is asked to complete it based on their knowledge of the patient's behavior (Kawata and Revicki, in press). Patient functioning is assessed in socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviors; an overall global rating is provided (0 to 100 scale). The PSP overlaps conceptually with the SOFI and was included as a construct validity measure for that reason.

retest global domain and overall global scores to evaluate test–retest reliability. An ICC of N 0.70 is considered acceptable. Inter-rater reliability was evaluated based on same-day SOFI administration to an independent, randomly selected 25% subset of informant/patient dyads. Extent of agreement between the two interviewers was evaluated via ICCs using a fixed effects model. Agreement between SOFI-P and SOFI-I scores for the full sample was also examined via ICCs. 2.5.2. Construct validity Examination of the pattern and magnitude of relationships among similar and dissimilar measures provides the basis for evaluating construct validity (Hays and Revicki, 2005). Construct validity, specifically convergent validity, of the SOFI-P and the SOFI-I was evaluated through examining relationships with QLS, PETiT, and PSP scores using Spearman correlation coefficients. Correlations between global domain and overall global scores from the SOFI and the total and subscale scores of the QLS and the PETiT were calculated. The a priori expectation was that correlation between SOFI and QLS would exceed that between SOFI and PETiT, given slightly greater conceptual overlap between functional outcomes measured by the QLS and SOFI. For both measures, low to moderate correlations (r = 0.30–0.50) were expected. Correlations between SOFI and PSP scores were used to examine the construct validity and were expected to be in the moderate to high range (r N 0.50). To address known-groups validity, subjects were stratified into two severity groups based on median split of PANSS scores (below the median and equal to and above the median) and SOFI global scores were compared by severity level using t-tests. This was done separately for all PANSS subscales (median positive = 16.0; median negative = 18.0; median general = 33.0). The hypothesis was that there would be significant differences in SOFI-measured functioning when patients with more symptoms as measured by the PANSS were compared to patients with fewer symptoms.

Table 2 Patient and informant demographic characteristics Characteristic

2.5.1. Reliability The test–retest reliability of SOFI scores was evaluated across an interval of 1–2weeks in a random sample of approximately 25% of the study informant/patient dyads. Intraclass correlations coefficients (ICC) and change scores using paired t-tests were calculated between the initial and

Patients

Informants

N = 104

N = 104

Age

Mean (st. dev.) Range

42.3 (13.0) 18.0–74.0

47.4 (13.9) 22.0–80.0

Gender (n, %)

Male

69 (66.3%)

30 (28.8%)

Race/ethnicity (n, %)

African–American Caucasian

41 (39.4%) 57 (54.8%)

29 (27.9%) 67 (64.4%)

Employment status (n, %)

Employed for pay, full/part time

24 (23%)

Hospitalizations in previous 12 month (%)

0 1 N1

83 (79.8%) 12 (11.5%) 9 (8.7%)

Residential status (n, %)

Unrestricted Semi-restricted Restricted

51 (49.0%) 21 (20.2%) 32 (30.8%)

2.5. Statistical analyses All analyses were performed using SAS version 8.02. Demographic and clinical information were evaluated using descriptive statistics. Scoring was performed according to the guidelines for each questionnaire, and significance was set at p ≤ 0.05.

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3. Results

Table 3 Test–retest and inter-rater reliability of the SOFI global scores

Test–retest Domain

Inter-rater reliability

3.1. Demographic and clinical characteristics

Patient– informant agreement

ICC (n = 104) ICC ICC ICC ICC patients informants patients informants (n = 25) (n = 23) (n = 26) (n = 26)

0.89 Living situation global rating

0.94

0.66

0.70

0.78

IADL global rating

0.89

0.94

0.73

0.79

0.74

0.66 Productive activities global rating

0.88

0.53

0.52

0.80

0.72 Social function global rating

0.87

0.63

0.50

0.65

Overall global score

0.94

0.73

0.73

0.85

0.83

A total of 104 dyads were recruited from 9 sites; 83 (79.8%) were diagnosed with schizophrenia and 21 (20.2%) diagnosed with schizoaffective disorder (Table 2). Sites recruited between 8 and 22 patients each. Living situation was unevenly distributed across all three categories. The majority of caregiver informants were female (72.2%) and 39.4% of informants lived with the patient (Table 2). Most patients (76%) reporting residence in an unrestricted living situation lived with family or friends. PANSS scores were reflective of a stable non-acute population with a mean score of 17.1 (SD = 5.8) on the PANSS Positive Scale and 18.7 (SD = 6.5) on the PANSS Negative Scale. Z-statistics for the BACS scores confirmed that this schizophrenic population was similar to other schizophrenic populations in the literature with regards to cognitive impairment (Keefe et al., 2004). 3.2. Test–retest reliability

Inter-rater reliability interviews were conducted on the same day, therefore respondent fatigue may have effected ratings. Information about regular productive activities may be difficult to obtain from the patient.

We also hypothesized that differences in cognitive function would be associated with significantly different SOFI global domain scores. The BACS composite score was stratified into high and low BACS score groups using the mean score, to test if the group with more cognitive impairment would have lower scores on the SOFI. Between-group differences in SOFI scores were evaluated with analysis of variance using the three living environment levels as a proxy for functioning in the community. We expected significant differences in SOFI scores between groups, with the more restricted groups having significantly lower SOFI scores than the unrestricted group. Finally we examined SOFI global scores by CGI-rated clinical severity with the expectation that less severe patients would have significantly higher SOFI scores.

Twenty-six patient–informant dyads participated in the test–retest reliability component of the study. ICCs for the SOFI-P ranged from 0.72 (Social Functioning) to 0.89 (IADLs); those for the SOFI-I ranged from 0.87 (Social Functioning) to 0.94 (Living Situation, IADLs) (Table 3). Test–retest reliability was also examined by type of caregiver (data not shown); family/friends (n = 12) versus paid caregiver (n = 14). ICCs for family and friends ranged from 0.75 (Productive Activities) to 0.98 (Living Situation) while for paid caregivers the ICCs ranged from 0.77 (Social Function) to 0.93 (IADLs). 3.3. Patient–informant concordance Agreement between the SOFI-P and SOFI-I on the global scores was good for three of the four domains. ICCs were 0.65 for Social Functioning, 0.74 for IADLs, 0.78 for Living Situation, 0.80 for Productive Activities, and 0.85 for the overall global score. No significant differences were found between mean SOFI domain scores.

Table 4 Relationship between SOFI domain scores and QLS scores

QLS total score QLS interpersonal relations QLS instrumental role QLS intrapsychic foundations QLS common objects and activities QLS intrapsychic foundations & common objects/activities PETiT Summary Score Quality of Life PETiT summary score medications PSP total score All p-values b 0.001 for all correlations.

Living situation global rating

IADLs global rating

Productive activities global rating

Social function global rating

Overall global score

Patient version

Informant version

Patient version

Informant version

Patient version

Informant version

Patient version

Informant version

Patient version

Informant version

0.579 0.438 0.498 0.530 0.612 0.602

0.515 0.418 0.400 0.476 0.521 0.535

0.699 0.519 0.602 0.677 0.568 0.717

0.547 0.431 0.469 0.531 0.461 0.571

0.652 0.417 0.679 0.614 0.430 0.630

0.622 0.420 0.655 0.568 0.437 0.584

0.673 0.691 0.444 0.517 0.453 0.554

0.540 0.500 0.386 0.437 0.351 0.464

0.612 0.683 0.692 0.590 0.734 0.778

0.520 0.594 0.616 0.499 0.645 0.671

0.220 0.162 0.623

0.250 0.207 0.641

0.359 0.275 0.619

0.347 0.233 0.675

0.302 0.272 0.646

0.290 0.252 0.757

0.254 0.153 0.583

0.252 0.175 0.594

0.365 0.290 0.741

0.365 0.285 0.819

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Fig. 2. A. Mean SOFI-P Global Scores by PANSS Positive Score-Based Groups. High = PANSS Positive score above and equal overall median of PANSS Positive. Low = PANSS Positive score below overall median of PANSS Positive. B. Mean SOFI-P Global Scores by PANSS Negative Score-Based Groups. High= PANSS Negative score above or equal overall median of PANSS Negative. Low = PANSS Negative score below overall median of PANSS Negative. C. Mean SOFI-P Global Scores by PANSS General Psychopathology Score-Based Groups. High= PANSS score above and equal overall median. Low = PANSS score below overall median.

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Fig. 3. Mean SOFI-P Global Scores by BACS Score-Based Groups. High = BACS overall Z score above and equal overall mean of BACS Z score (mean = −1.3). Low = BACS overall Z score below overall mean of BACS Z score (mean = − 1.3). SOFI scores on y-axis. All p values b0.05.

3.4. Inter-rater reliability Twenty-five patient–informant dyads participated in the inter-rater reliability component of the study. ICCs ranged from 0.53 (Productive Activities) to 0.73 (IADLs) for the patients and 0.50 (Social Functioning) to 0.79 (IADLs) for the informants (Table 3). 3.5. Construct validity 3.5.1. Convergent Validity Based on the Spearman correlation coefficients, all SOFI-P global scores were significantly correlated (p b 0.001) with QLS scale scores (Table 4). Correlations between the QLS and the SOFI were somewhat lower for informants than for patients.

Correlations between the SOFI Global ratings and the PETiT Summary Scores were low to moderate for both the patient (r = 0.15 to 0.37) and informant versions (r = 0.18 to 0.37) (Table 4). The lowest correlation (r = 0.15; ns) was found between the SOFI-P Social Function domain and the PETiT Medication score while the highest correlation (r = 0.37; p b 0.001) was between the SOFI overall global score (both SOFI-I and SOFI-P) and the PETiT quality of life score (Table 4). As expected, given the conceptual overlap between the SOFI and the PSP, correlations were moderate to high (range 0.58 to 0.76; all p b 0.0001) depending on domain of interest with slightly higher coefficients in general for the informant version (Table 4). 3.5.2. Known groups validity Almost all mean SOFI global ratings comparisons were statistically significantly different by PANSS scores. Mean

Table 5 Mean SOFI global scores by living environment

Patient Living situation global rating IADLs global rating Productive activities global rating Social function global rating Overall global score Informant Living situation global rating IADLs global rating Productive activities global rating Social function global rating Overall global score

Unrestricted mean (SD) 1

Semi-restricted mean (SD) 2

Restricted mean (SD) 3

Overall F value

p values

Significant differences 4

82.00 (15.17) 72.31 (20.89) 66.76 (27.37)

77.29 (11.06) 70.00 (19.88) 72.15 (23.22)

53.13 (18.63) 47.84 (17.06) 53.55 (23.42)

34.916 16.456 3.932

b 0.001 b 0.001 0.022

a, b a, b a

67.90 (23.28) 72.15 (17.66)

72.52 (17.50) 73.48 (15.79)

48.13 (18.54) 50.19 (15.35)

11.742 19.381

b 0.001 b 0.001

a, b a, b

81.63 (12.85) 71.25 (17.74) 64.37 (27.20)

79.14 (11.27) 73.71 (15.33) 74.45 (17.08)

54.44 (16.55) 48.41 (15.22) 50.27 (24.37)

40.887 22.666 6.178

b 0.001 b 0.001 0.002

a, b a, b a, b

69.47 (17.78) 71.71 (14.81)

71.71 (16.51) 75.36 (12.60)

49.00 (18.40) 49.99 (15.22)

15.838 26.136

b 0.001 b 0.001

a a, b

a p b 0.05: Restricted versus Semi-Restricted. b p b 0.05: Restricted versus Unrestricted. 1 N ranges from 49–51 for Unrestricted. 2 N ranges from 20–21 for Semi-restricted. 3 N ranges from 30–32 for Restricted. 4 Using Scheffe's adjustment.

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SOFI global ratings were significantly different for the PANSS Positive based groups (Fig. 2A; p b 0.001 to p = 0.018). Groups based on the PANSS Negative scale (Fig. 2B) demonstrated statistically significant mean differences for the SOFI-P (all p b 0.05) and for three of the four domains for the SOFI-I (all p b 0.01 except for Productive Activities). Mean SOFI-P and SOFI-I scores were significantly different between high and low scores on the PANSS General Psychopathology scale (all p b 0.05) (Fig. 2C). Mean SOFI-P and SOFI-I global scores were differed significantly for the BACs defined groups (all p b 0.05). See Fig. 3 for SOFI-P (SOFI-I data not shown). SOFI scores also differed between restricted and semirestricted living situation groups for all domains (SOFI-P and SOFI-I, all p b 0.05). Restricted and unrestricted groups also differed on SOFI Living Situation, IADLs, and Social Functioning Global scores (Table 5). Comparisons across all global ratings for the SOFI-P and SOFI-I demonstrated significant differences between borderline and moderately ill patients as measured by the CGIS (p b 0.05). Statistically significant differences were found in SOFI patient and informant IADLs scores and SOFI-I Living Situation scores for borderline versus severe groups (p b 0.05). 4. Discussion The SOFI was developed as an interviewer-rated measure of objective functioning in patients with schizophrenia. This report summarizes the systematic development and the reliability and validity of the SOFI-P and the SOFI-I. These results indicate that the SOFI has good evidence supporting reliability and construct validity, and may be a useful measure of functional outcomes in schizophrenia. The SOFI was designed for either patients or other informants to serve as respondents, and use of multiple sources of information is encouraged (e.g., medical records, other written records, patient, informants). The patient was always interviewed first so it was possible that the informant version ratings were completed with the benefit of information from the patient interview as well as the informant. Instructions emphasize that prior knowledge of the patient be included in both the patient and informant ratings. Patient respondent data appeared sufficient to assess functional outcomes as there was good concordance in three out of the four domains between informant-derived and patient-derived scores (ICCs ranged from 0.65 to 0.85). It should be noted, however, that since the same interviewer may have administered both the SOFI-I and SOFI-P and the other clinical rating scales, conclusions about between-version concordance and construct validity are somewhat limited. However, acceptable concordance was observed suggesting that the informant and the patient are both adequate respondents for this instrument. The ability to use the patient-reporting only would be of great advantage to clinical trials since many schizophrenic patients lack a caregiver or informant. Future research on the SOFI should focus on the concordance between the SOFI-P and SOFI-I ratings based on independent clinical interviews.

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Test–retest reliability indicating the stability of the global ratings was good even when evaluated separately by type of caregiver (family/friend versus paid caregiver). Inter-rater reliability was lower but was not assessed optimally in this study; the result could relate to variation in the interviewer's prior knowledge of the patient and/or respondent fatigue. Staffing constraints at the sites prevented evaluation from two raters during the same interview. The SOFI-P produced a low ICC coefficient in productive activities perhaps due to the difficulty in eliciting information about regular activities from the patient. Previous studies (Bowie et al., 2007) have also found that patient–informant convergence was lowest for productive activities. Inter-rater reliability for informants was quite low for social functioning, likely due to the fact that many informants did not see the patient often enough to know much about the quantity and quality of their social interactions. Evidence supporting construct validity was acceptable. As expected, correlations between the SOFI and both the QLS and PSP were moderate to high due to the conceptual overlap of the instruments. The QLS measures functional aspects of quality of life, and correlations between the QLS total score and SOFI-P domains of IADLs, productive activities and social function were all higher than 0.60. While correlations between these domains and the SOFI-I were slightly lower, they were all greater than 0.50. Construct validity results may have been affected by having the same rater conduct the SOFI and the QLS interviews, artificially inflating the correlation coefficients. The PSP measures patients' functioning in several areas similar to the SOFI, and correlations here were all above 0.60 (except for social function domain). When examining the relationship between the SOFI and the PETiT, low to low– moderate correlations indicate that there is minimal conceptual overlap as expected and these instruments are measuring related but different concepts. Even among this fairly stable schizophrenia population, the SOFI was able to differentiate between patients with a high and low degree of psychopathology as well as between patients with lower or higher degrees of cognitive impairment. Patients with more impairment in clinical symptoms or cognitive function were rated as having worse functional outcomes using the SOFI-P. This relationship has been inconsistently observed in previous studies of function and positive symptoms. Some studies (Green, 1996) have demonstrated no significant association between psychotic symptoms and function while others have demonstrated a weak to moderate relationship (Mohamed et al., 2008). Previous work has also demonstrated that cognitive impairment is associated with functional impairment in schizophrenia (Leung et al., 2008; Mohamed et al., 2008). Nevertheless we found a significant relationship between positive symptoms and SOFI scores. The SOFI-I also demonstrated differences by cognitive impairment and PANSS scores. We hypothesized that the more restricted the living situation, the lower the scores on a functional impairment instrument, and this was confirmed in this study. We found that there were significantly different mean scores for patients who lived in restricted versus semi-restricted housing, as well as between restricted and unrestricted living environments. However, the SOFI scores did not

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differentiate between unrestricted and semi-restricted housing groups. While we were unable to measure responsiveness in this study, the ability of the SOFI to distinguish among different levels of cognitive, symptomatic, and restricted living environments indicates likely sensitivity to change in functional status over time. The responsiveness of the SOFI will need to be determined in future research. The patient population recruited for this study may differ somewhat from that generally recruited for a clinical trial. Although the study patients had been diagnosed with schizophrenia for a considerable time, they were relatively clinically stable and experienced few previous hospitalizations in the prior year. Compared with the subjects included in the CATIE study (Lieberman et al., 2005), the patients in this study were roughly similar in terms of demographic characteristics, but had fewer previous hospitalizations in the past year and PANSS and CGI-S scores indicated less impairment. Patients in this study did present a similar degree of cognitive impairment compared to other schizophrenia populations based on BACS score (Keefe et al., 2004). The intent of the SOFI development effort was to develop a functional outcome measure that could be used in clinical trials and other clinical studies evaluating interventions for cognitive impairment associated with schizophrenia. The original intent was not to develop a measure that could be used with individual patients for clinical decision-making, although it is possible that the SOFI could be used with individual patients. Additional research would be needed, given that use for individual patient decision-making would require higher reliabilities and would need to be demonstrated in further studies. Based on the psychometric evidence, the SOFI may be used in clinical trials and for group comparisons. Several limitations should be considered when interpreting this study. First, these results are based on a relatively small sample of patients with schizophrenia, and further research is needed to examine measurement qualities in different and larger schizophrenia samples. Second, this sample may not be generalizable to more unstable patients entered into clinical trials. Although this sample is comparable on demographic characteristics to patients participating in the CATIE study (Lieberman et al., 2005), they had lower PANSS and CGI-S scores. Additional research on more heterogeneous samples of schizophrenia patients is required to make conclusions about psychometric performance across a wider spectrum of disease severity. This cohort may represent the stable, moderately symptomatic patients who are candidates for co-administered treatment for cognition impairment (Buchanan et al., 2005). Previous studies have found that patient self-report is unreliable and interviewer impression based on interviews with patients and informants is better for establishing convergent validity of a measure in schizophrenia (Keefe et al., 2006). It is important to note then that, at some sites, the SOFI interviewers also conducted the clinical interviews (PANSS, QLS, etc.), possibly increasing convergence. The SOFI is a new, psychometrically sound, method for measuring function in patients with schizophrenia. The

SOFI was systematically developed with input from clinicians, patients, and formal caregivers, and demonstrates good test–retest reliability— and for most scores, acceptable inter-rater reliability with preliminary evidence demonstrating acceptable construct validity. The SOFI takes a trained interviewer approximately 30–45 minutes to administer. Future research should further examine patient and informant concordance and inter-rater reliability. Additional research is needed to determine whether the SOFI is an effective measure of change in clinical trials. However, based on the known group validity analyses, it is likely that the SOFI will prove to be sensitive to changes in symptom severity, and thus will provide a valid assessment method for this purpose. Additional research, particularly longitudinal research tracking interventions, is necessary to make definitive recommendations regarding the identification of clinically relevant change in SOFI scores. Role of funding source Eli Lilly Incorporated provided funding for this research. Research staff from Eli Lilly participated in study design and analysis as well as manuscript review. Contributors Drs. Kleinman, Revicki, and Frank designed the study, wrote the protocol, oversaw the conduct of the study, wrote the statistical analysis plan, and oversaw the analysis and interpretation. Dr. Kleinman wrote the first draft of the manuscript. Drs. Dubé, Zhao, Mohs, Kinon, and Bowman reviewed the study design and analysis, and contributed to the manuscript. Drs. Carpenter, Green, Keefe, and Harvey reviewed the protocol and the analytic approach, and contributed to the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest Drs. Kleinman, Revicki, and Frank are employed by United BioSource Corporation, recipient of a research contract from Eli Lilly to support this project. Drs. Zhao, Dube, Kinon, and Mohs are employees of Eli Lilly. Drs. Lieberman, Carpenter, Harvey, Green, and Keefe received advisory fees for meeting participation. The academic authors did not receive any additional funds for manuscript development. The authors had sole responsibility for manuscript preparation. Acknowledgements We would like to thank all the participants in the initial consultant meeting, including Dr. William Carpenter, Dr. Michael Green, Dr. Doug Galasko, Dr. Alise Medalia, Dr. Goran Sedvall, Dr. Dieter Naber, Dr. Karen Ritchie, and Dr. Bruno Falissard. We also would like to thank the CATIE sites that participated in this study, which includes the following sites and principal investigators: Valley Mental Health Psychopharmacology Research Center (Michael Stevens, MD); University of North Carolina (Scott Stroup, MD, MPH); New Mexico VA Healthcare System (Jose Canive, MD); Connecticut Mental Health Center, Yale University (Cyril D'Souza MD); University of Rochester Medical Center Strong Ties Community Support Program (Steven Lamberti, MD); Duke University Medical Center John Umstead Hospital (Joseph McEVoy MD, William Wilson PhD); University of Miami School of Medicine Department of Psychiatry (Richard M. Steinbook, MD); University of Cincinnati Medical Center (Henry Nasrallah, MD); Freedom Trail Clinic (MGH) Schizophrenia Research Program (Donald Goff, MD). We are also grateful to all the study coordinators and raters at each site. In addition we would like to thank Fritz Hamme, Production Assistant at United BioSource Corporation, for production assistance with the manuscript. The SOFI is available for use by all researchers by contacting Eli Lilly. The complete package of information on the SOFI patient and informant versions, and administration and scoring manual can be obtained by contacting Sanjay Dubé ([email protected]) at Eli Lilly.

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