Methods for questionnaire design: a taxonomy linking procedures to test goals.

BACKGROUND: In the clinical field, the use of questionnaires is ubiquitous, and many different methods for constructing them are available. The reason for using a specific method is usually lacking, and a generally accepted classification of methods is not yet available. To guide test developers and users, this article presents a taxonomy for methods of questionnaire design which links the methods to the goal of a test. METHODS: The taxonomy assumes that construction methods are directed towards psychometric aspects. Four stages of test construction are distinguished to describe methods: concept analysis, item production, scale construction, and evaluation; the scale construction stage is used for identifying methods. It distinguishes six different methods: the rational method utilizes expert judgments to ensure face validity. The prototypical method uses prototypicality judgments to ensure process validity. In the internal method, item sets are selected that optimize homogeneity. The external method optimizes criterion validity by selecting items that best predict an external criterion. Under the construct method theoretical considerations are used to optimize construct validity. The facet method is aimed at optimizing content validity through a complete representation of the concept domain. CONCLUSION: The taxonomy is comprehensive, constitutes a useful tool for describing procedures used in questionnaire design, and allows for setting up a test construction plan in which the priorities among psychometric aspects are made explicit.

Some recommendations for developing multidimensional computerized adaptive tests for patient-reported outcomes.

PURPOSE: Multidimensional item response theory and computerized adaptive testing (CAT) are increasingly used in mental health, quality of life (QoL), and patient-reported outcome measurement. Although multidimensional assessment techniques hold promises, they are more challenging in their application than unidimensional ones. The authors comment on minimal standards when developing multidimensional CATs. METHODS: Prompted by pioneering papers published in QLR, the authors reflect on existing guidance and discussions from different psychometric communities, including guidelines developed for unidimensional CATs in the PROMIS project. RESULTS: The commentary focuses on two key topics: (1) the design, evaluation, and calibration of multidimensional item banks and (2) how to study the efficiency and precision of a multidimensional item bank. The authors suggest that the development of a carefully designed and calibrated item bank encompasses a construction phase and a psychometric phase. With respect to efficiency and precision, item banks should be large enough to provide adequate precision over the full range of the latent constructs. Therefore CAT performance should be studied as a function of the latent constructs and with reference to relevant benchmarks. Solutions are also suggested for simulation studies using real data, which often result in too optimistic evaluations of an item bank's efficiency and precision. DISCUSSION: Multidimensional CAT applications are promising but complex statistical assessment tools which necessitate detailed theoretical frameworks and methodological scrutiny when testing their appropriateness for practical applications. The authors advise researchers to evaluate item banks with a broad set of methods, describe their choices in detail, and substantiate their approach for validation.

Measurement versus prediction in the construction of patient-reported outcome questionnaires: can we have our cake and eat it?

BACKGROUND: Two important goals when using questionnaires are (a) measurement: the questionnaire is constructed to assign numerical values that accurately represent the test taker's attribute, and (b) prediction: the questionnaire is constructed to give an accurate forecast of an external criterion. Construction methods aimed at measurement prescribe that items should be reliable. In practice, this leads to questionnaires with high inter-item correlations. By contrast, construction methods aimed at prediction typically prescribe that items have a high correlation with the criterion and low inter-item correlations. The latter approach has often been said to produce a paradox concerning the relation between reliability and validity [1-3], because it is often assumed that good measurement is a prerequisite of good prediction. OBJECTIVE: To answer four questions: (1) Why are measurement-based methods suboptimal for questionnaires that are used for prediction? (2) How should one construct a questionnaire that is used for prediction? (3) Do questionnaire-construction methods that optimize measurement and prediction lead to the selection of different items in the questionnaire? (4) Is it possible to construct a questionnaire that can be used for both measurement and prediction? ILLUSTRATIVE EXAMPLE: An empirical data set consisting of scores of 242 respondents on questionnaire items measuring mental health is used to select items by means of two methods: a method that optimizes the predictive value of the scale (i.e., forecast a clinical diagnosis), and a method that optimizes the reliability of the scale. We show that for the two scales different sets of items are selected and that a scale constructed to meet the one goal does not show optimal performance with reference to the other goal. DISCUSSION: The answers are as follows: (1) Because measurement-based methods tend to maximize inter-item correlations by which predictive validity reduces. (2) Through selecting items that correlate highly with the criterion and lowly with the remaining items. (3) Yes, these methods may lead to different item selections. (4) For a single questionnaire: Yes, but it is problematic because reliability cannot be estimated accurately. For a test battery: Yes, but it is very costly. Implications for the construction of patient-reported outcome questionnaires are discussed.

Development of Short-Form Versions of the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R): A Proof-of-Principle Study.

BACKGROUND: The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a 24-item questionnaire designed to assess risk of aberrant medication-related behaviors in chronic pain patients. The introduction of short forms of the SOAPP-R may save time and increase utilization by practitioners. OBJECTIVE: To develop and evaluate candidate SOAPP-R short forms. DESIGN: Retrospective study. SETTING: Pain centers. SUBJECTS: Four hundred and twenty-eight patients with chronic noncancer pain. METHODS: Subjects had previously been administered the full-length version of the SOAPP-R and been categorized as positive or negative for aberrant medication-related behaviors via the Aberrant Drug Behavior Index (ADBI). Short forms of the SOAPP-R were developed using lasso logistic regression. Sensitivity, specificity, and area under the curve (AUC) of all forms were calculated with respect to the ADBI using the complete data set, training-test analysis, and 10-fold cross-validation. The coefficient alpha of each form was also calculated. An external set of 12 pain practitioners reviewed the forms for content. RESULTS: In the complete data set analysis, a form of 12 items exhibited sensitivity, specificity, and AUC greater than or equal to those of the full-length SOAPP-R (which were 0.74, 0.67, and 0.76, respectively). The short form had a coefficient alpha of 0.76. In the training-test analysis and 10-fold cross-validation, it exhibited an AUC value within 0.01 of that of the full-length SOAPP-R. The majority of external practitioners reported a preference for this short form. CONCLUSIONS: The 12-item version of the SOAPP-R has potential as a short risk screener and should be tested prospectively.

The Four-Dimensional Symptom Questionnaire (4DSQ) in the general population: scale structure, reliability, measurement invariance and normative data: a cross-sectional survey.

BACKGROUND: The Four-Dimensional Symptom Questionnaire (4DSQ) is a self-report questionnaire measuring distress, depression, anxiety and somatization with separate scales. The 4DSQ has extensively been validated in clinical samples, especially from primary care settings. Information about measurement properties and normative data in the general population was lacking. In a Dutch general population sample we examined the 4DSQ scales' structure, the scales' reliability and measurement invariance with respect to gender, age and education, the scales' score distributions across demographic categories, and normative data. METHODS: 4DSQ data were collected in a representative Dutch Internet panel. Confirmatory factor analysis was used to examine the scales' structure. Reliability was examined by Cronbach's alpha, and coefficients omega-total and omega-hierarchical. Differential item functioning (DIF) analysis was used to evaluate measurement invariance across gender, age and education. RESULTS: The total response rate was 82.4 % (n = 5273/6399). The depression scale proved to be unidimensional. The other scales were best represented as bifactor models consisting of a large general factor and one or more smaller specific factors. The general factors accounted for more than 95 % of the reliable variance of the scales. Reliability was high (≥0.85) by all estimates. The distress-, depression- and anxiety scales were invariant across gender, age and education. The somatization scale demonstrated some lack of measurement invariance as a result of decreased thresholds for some of the items in young people (16-24 years) and increased thresholds in elderly people (65+ years). The somatization scale was invariant regarding gender and education. The 4DSQ scores varied significantly across demographic categories, but the explained variance was small (<6 %). Normative data were generated for gender and age categories. Approximately 17 % of the participants scored above average on de distress scale, whereas 12 % scored above average on de somatization scale. Percentages of people scoring high enough on depression or anxiety as to suspect the presence of depressive or anxiety disorder were 4.1 and 2.5 respectively. CONCLUSIONS: Evidence supports reliability and measurement invariance of the 4DSQ in the general Dutch population. The normative data provided in this study can be used to compare a subject's 4DSQ scores with a general population reference group.

On the effect of adding clinical samples to validation studies of patient-reported outcome item banks: a simulation study.

PURPOSE: To increase the precision of estimated item parameters of item response theory models for patient-reported outcomes, general population samples are often enriched with samples of clinical respondents. Calibration studies provide little information on how this sampling scheme is incorporated into model estimation. In a small simulation study the impact of ignoring the oversampling of clinical respondents on item and person parameters is illustrated. METHOD: Simulations were performed using two scenarios. Under the first it was assumed that regular and clinical respondents form two distinct distributions; under the second it was assumed that they form a single distribution. A synthetic item bank with quasi-trait characteristics was created, and item scores were generated from this bank for samples with varying percentages of clinical respondents. Proper (using a multi-group model, and sample weights, respectively, for Scenarios 1 and 2) and improper (ignoring oversampling) approaches for dealing with the clinical sample were contrasted using correlations and differences between true and estimated parameters. RESULTS: Under the first scenario, ignoring the sampling scheme resulted in overestimation of both item and person parameters with bias decreasing with higher percentages of clinical respondents. Under the second, location and person parameters were underestimated with bias increasing in size with increasing percentage of clinical respondents. Under both scenarios, the standard error of the latent trait estimate was generally underestimated. CONCLUSION: Ignoring the addition of extra clinical respondents leads to bias in item and person parameters, which may lead to biased norms and unreliable CAT scores. An appeal is made for researchers to provide more information on how clinical samples are incorporated in model estimation.

Shortening the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R): A Proof-of-Principle Study for Customized Computer-Based Testing.

BACKGROUND: The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a 24-item self-report instrument that was developed to aid providers in predicting aberrant medication-related behaviors among chronic pain patients. Although the SOAPP-R has garnered widespread use, certain patients may be dissuaded from taking it because of its length. Administrative barriers associated with lengthy questionnaires further limit its utility. OBJECTIVE: To investigate the extent to which two techniques for computer-based administration (curtailment and stochastic curtailment) reduce the average test length of the SOAPP-R without unduly affecting sensitivity and specificity. DESIGN: Retrospective study. SETTING: Pain management centers. SUBJECTS: Four hundred and twenty-eight chronic non-cancer pain patients. METHODS: Subjects had taken the full-length SOAPP-R and been classified by the Aberrant Drug Behavior Index (ADBI) as having engaged or not engaged in aberrant medication-related behavior. Curtailment and stochastic curtailment were applied to the data in post-hoc simulation. Sensitivity and specificity with respect to the ADBI, as well as average test length, were computed for the full-length test, curtailment, and stochastic curtailment. RESULTS: The full-length SOAPP-R exhibited a sensitivity of 0.745 and a specificity of 0.671 for predicting the ADBI. Curtailment reduced the average test length by 26% while exhibiting the same sensitivity and specificity as the full-length test. Stochastic curtailment reduced the average test length by as much as 65% while always exhibiting sensitivity and specificity for the ADBI within 0.035 of those of the full-length test. CONCLUSIONS: Curtailment and stochastic curtailment have potential to improve the SOAPP-R's efficiency in computer-based administrations.

Variable length testing using the ordinal regression model.

Health questionnaires are often built up from sets of questions that are totaled to obtain a sum score. An important consideration in designing questionnaires is to minimize respondent burden. An increasingly popular method for efficient measurement is computerized adaptive testing; unfortunately, many health questionnaires do not meet the requirements for this method. In this paper, a new sequential method for efficiently obtaining sum scores via the computer is introduced, which does not have such requirements and is based on the ordinal regression model. In the assessment, future scores are predicted from past responses, and when an acceptable level of uncertainty is achieved, the procedure is terminated. Two simulation studies were performed to illustrate the usefulness of the procedure. The first used artificially generated symptom scores, and the second was a post hoc simulation using real responses on the Center for Epidemiologic Studies Depression scale. In both studies, the sequential method substantially reduced the respondent burden while maintaining a high sum score quality. Benefits and limitations of this new methodology are discussed.

Shortening the Current Opioid Misuse Measure via computer-based testing: a retrospective proof-of-concept study.

BACKGROUND: The Current Opioid Misuse Measure (COMM) is a self-report questionnaire designed to help identify aberrant drug-related behavior in respondents who have been prescribed opioids for chronic pain. The full-length form of the COMM consists of 17 items. Some individuals, especially compromised individuals, may be deterred from taking the full questionnaire due to its length. This study examined the use of curtailment and stochastic curtailment, two computer-based testing approaches that sequentially determine the test length for each individual, to reduce the respondent burden of the COMM without compromising sensitivity and specificity. METHODS: Existing data from n = 415 participants, all of whom had taken the full-length COMM and had been classified via the Aberrant Drug Behavior Index (ADBI), were divided into training (n = 214) and test (n = 201) sets. Post-hoc analysis of the test set was performed to evaluate the screening results and test lengths that would have been obtained, if curtailment or stochastic curtailment had been used. Sensitivity, specificity, and average test length were calculated for each method and compared with the corresponding values of the full-length test. RESULTS: The full-length COMM had a sensitivity of 0.703 and a specificity of 0.701 for predicting the ADBI. Curtailment reduced the average test length by 22% while maintaining the same sensitivity and specificity as the full-length COMM. Stochastic curtailment reduced the average test length by as much as 59% while always obtaining a sensitivity of at least 0.688 and a specificity of at least 0.701 for predicting the ADBI. CONCLUSIONS: Curtailment and stochastic curtailment have the potential to achieve substantial reductions in respondent burden without compromising sensitivity and specificity. The two sequential methods should be considered for future computer-based administrations of the COMM.

The crucial role of the predictability of motor response in visuomotor deficits in very preterm children at school age.

AIM: We aimed to clarify the underpinnings of widespread visuomotor deficits in very preterm children. METHOD: Fifty-eight very preterm children (26 males, 32 females; mean [SD] age 7 y 6 mo [5 mo], gestational age 29.2 wks [1.6]; birthweight 1237 g [336]), recruited from a tertiary level neonatal intensive care unit, and 64 age-matched, comparison children born at term (28 males, 36 females; mean age [SD] 7 y 8 mo [7 mo]) participated. IQ was measured using a short form of the Wechsler Intelligence Scale for Children (3rd edition). A research diagnosis of developmental coordination disorder (DCD) was defined as a score below the 15th centile on the Movement Assessment Battery for Children. Visuomotor performance was assessed using a computerized task, in which children followed a predictable (structured condition) or an unpredictable (non-structured condition) trail on a touch screen using their index finger. RESULTS: Forty-six per cent of the very preterm children had a research diagnosis of DCD, compared with 16% of children born at term (p<0.001, odds ratio 4.69 [95% CI 2.01-10.99]). No group difference in visuomotor performance was present for the structured condition. In the non-structured condition, children born very preterm with and without a research diagnosis of DCD had poorer visuomotor performance than those born at term. INTERPRETATION: The predictability of the required motor response plays a crucial role in visuomotor deficits in very preterm children, regardless of DCD status.

A proof of principle for using adaptive testing in Routine Outcome Monitoring: the efficiency of the Mood and Anxiety Symptoms Questionnaire -Anhedonic Depression CAT.

BACKGROUND: In Routine Outcome Monitoring (ROM) there is a high demand for short assessments. Computerized Adaptive Testing (CAT) is a promising method for efficient assessment. In this article, the efficiency of a CAT version of the Mood and Anxiety Symptom Questionnaire, - Anhedonic Depression scale (MASQ-AD) for use in ROM was scrutinized in a simulation study. METHODS: The responses of a large sample of patients (N = 3,597) obtained through ROM were used. The psychometric evaluation showed that the items met the requirements for CAT. In the simulations, CATs with several measurement precision requirements were run on the item responses as if they had been collected adaptively. RESULTS: CATs employing only a small number of items gave results which, both in terms of depression measurement and criterion validity, were only marginally different from the results of a full MASQ-AD assessment. CONCLUSIONS: It was concluded that CAT improved the efficiency of the MASQ-AD questionnaire very much. The strengths and limitations of the application of CAT in ROM are discussed.

Construct validity, responsiveness, and utility of change indicators of the Dutch-Flemish PROMIS item banks for depression and anxiety administered as computerized adaptive test (CAT): A comparison with the Brief Symptom Inventory (BSI).

We evaluated construct validity, responsiveness, and utility of change indicators of the Dutch-Flemish PROMIS adult v1.0 item banks for Depression and Anxiety administered as computerized adaptive test (CAT). Specifically, the CATs were compared to the Brief Symptom Inventory (BSI) using pre- and re-test data of adult patients treated for common mental disorders (N = 400; median pre-to-re-test interval = 215 days). Construct validity was evaluated with Pearson's correlations and Cohen's ds; responsiveness with Pearson's correlations and pre-post effect sizes (ES); utility of change indicators with kappa coefficients and percentages of (dis)agreement. The results showed that the PROMIS CATs measure similar constructs as matching BSI scales. Under the assumption of measuring similar constructs, the CAT and BSI Depression scales were similarly responsive. For the Anxiety scales, we found a higher responsiveness for CAT (ES = 0.64) compared to the BSI (ES = 0.50). Finally, both CATs categorized the change scores of more patients as changed compared to matching BSI scales, indicating that the PROMIS CATs may be more able to detect actual change than the BSI. Based on these findings, the PROMIS CATs may be considered a modest improvement over matching BSI scales as tools for reviewing treatment progress with patients. We discuss several additional differences between the PROMIS CATs and the BSI to help test users choose instruments. These differences include the adopted measurement theory (Item Response Theory vs. Classical Test Theory), the mode of administration (CAT vs. fixed items), and the area of application (universal vs. predominantly clinical). (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Measurement invariance of the Center for Epidemiological Studies Depression Scale (CES-D) among Chinese and Dutch elderly.

BACKGROUND: Although previous studies using non- elderly groups have assessed the factorial invariance of the Center for Epidemiological Studies Depression Scale (CES-D) across different groups with the same social-cultural backgrounds, few studies have tested the factorial invariance of the CES-D across two elderly groups from countries with different social cultures. The purposes of this study were to examine the factorial structure of the CES-D, and test its measurement invariance across two different national elderly populations. METHODS: A total of 6806 elderly adults from China (n = 4903) and the Netherlands (n = 1903) were included in the final sample. The CES-D was assessed in both samples. Three strategies were used in the data analysis procedure. First, a confirmatory factor analysis (CFA) was carried out to determine the factor structures of the CES-D that best fitted the two samples. Second, the best fitting model was incorporated into a multi-group CFA model to test measurement invariance of the CES-D across the two population groups. Third, latent mean differences between the two groups were tested. RESULTS: The results of confirmatory factor analysis (CFA) showed: 1) in both samples, Radloff's four-factor model resulted in a significantly better fit and the four dimensions (somatic complaints, depressed affect, positive affect, and interpersonal problems) of the CES-D seem to be the most informative in assessing depressive symptoms compared to the single-, three-, and the second-order factor models; and 2) the factorial structure was invariant across the populations under study. However, only partial scalar and uniqueness invariance of the CES-D items was supported. Latent means in the partial invariant model were lower for the Dutch sample, compared to the Chinese sample. CONCLUSIONS: Our findings provide evidence of a valid factorial structure of the CES-D that could be applied to elderly populations from both China and the Netherlands, producing a meaningful comparison of total scores between the two elderly groups. However, for some specific factors and items, caution is required when comparing the depressive symptoms between Chinese and Dutch elderly groups.

Applying computerized adaptive testing to the CES-D scale: a simulation study.

In this paper we studied the appropriateness of developing an adaptive version of the Center of Epidemiological Studies-Depression (CES-D, Radloff, 1977) scale. Computerized Adaptive Testing (CAT) involves the computerized administration of a test in which each item is dynamically selected from a pool of items until a pre-specified measurement precision is reached. Two types of analyses were performed using the CES-D responses of a large sample of adolescents (N=1392). First, it was shown that the items met the psychometric requirements needed for CAT. Second, CATs were simulated by using the existing item responses as if they had been collected adaptively. CATs selecting only a small number of items gave results which, in terms of depression measurement and criterion validity, were only marginally different from the results of full CES-D assessment. It was concluded that CAT is a very fruitful way of improving the efficiency of the CES-D questionnaire. The discussion addresses the strengths and limitations of the application of CAT in mental health research.

Practical Significance of Longitudinal Measurement Invariance Violations in the Dutch-Flemish PROMIS Item Banks for Depression and Anxiety: An Illustration With Ordered-Categorical Data.

We investigated longitudinal measurement invariance in the Dutch-Flemish PROMIS adult v1.0 item banks for Depression and Anxiety using two clinical samples with mood and anxiety disorders (n = 640 and n = 528, respectively). Factor analysis was used to evaluate whether the item banks were sufficiently unidimensional at two test-occasions and whether the measured constructs remained the same over time. The results indicated that the item banks were sufficiently unidimensional, but the thresholds and residual variances of the constructs changed over time. However, using tentative rules of thumb, these invariance violations did not substantially affect the endorsement of a specific response category of a specific item at a specific test-occasion. Furthermore, the impact on the mean latent change scores of the item banks remained below the proposed cutoff value for substantial bias. These findings suggest that the invariance violations lacked practical significance for test-users, meaning that the item banks provide sufficiently invariant latent factor scores for use in clinical practice.

International application of PROMIS computerized adaptive tests: US versus country-specific item parameters can be consequential for individual patient scores.

OBJECTIVE: PROMIS offers computerized adaptive tests (CAT) of patient-reported outcomes, using a single set of US-based IRT item parameters across populations and language-versions. The use of country-specific item parameters has local appeal, but also disadvantages. We illustrate the effects of choosing US or country-specific item parameters on PROMIS CAT T-scores. STUDY DESIGN AND SETTING: Simulations were performed on response data from Dutch chronic pain patients (n = 1110) who completed the PROMIS Pain Behavior item bank. We compared CAT T-scores obtained with (1) US parameters; (2) Dutch item parameters; (3) US item parameters for DIF-free items and Dutch item parameters (rescaled to the US metric) for DIF items; (4) Dutch item parameters for all items (rescaled to the US metric). RESULTS: Without anchoring to a common metric, CAT T-scores cannot be compared. When scores were rescaled to the US metric, mean differences in CAT T-scores based on US vs. Dutch item parameters were negligible. However, 0.9%-4.3% of the T-score differences were larger than 5 points (0.5 SD). CONCLUSION: The choice of item parameters can be consequential for individual patient scores. We recommend more studies of translated CATs to examine if strategies that allow for country-specific item parameters should be further investigated.

A note on Youden's J and its cost ratio.

BACKGROUND: The Youden index, the sum of sensitivity and specificity minus one, is an index used for setting optimal thresholds on medical tests. DISCUSSION: When using this index, one implicitly uses decision theory with a ratio of misclassification costs which is equal to one minus the prevalence proportion of the disease. It is doubtful whether this cost ratio truly represents the decision maker's preferences. Moreover, in populations with a different prevalence, a selected threshold is optimal with reference to a different cost ratio. SUMMARY: The Youden index is not a truly optimal decision rule for setting thresholds because its cost ratio varies with prevalence. Researchers should look into their cost ratio and employ it in a decision theoretic framework to obtain genuinely optimal thresholds.

Determining at What Age Children Provide Sound Self-Reports: An Illustration of the Validity-Index Approach.

In psychological assessment of children, it is pivotal to establish from what age on self-reports can complement or replace informant reports. We introduce a psychometric approach to estimate the minimum age for a child to produce self-report data that is of similar quality as informant data. The approach makes use of statistical validity indicators such as person-fit and long-string indices, and can be readily applied to data commonly collected in psychometric studies of child measures. We evaluate and illustrate the approach, using self-report and informant-report data of the PedsQL, a pediatric health-related quality of life measure, from 651 child-mother pairs. To evaluate the approach, we tested various hypotheses about the validity of the self-report data, using the Gnp person-fit index as the validity indicator and the mother informant-data as a benchmark for validity. Results showed that Gnp discriminated between self-reports of younger and older children, between self-reports of children that completed the PedsQL alone or with a parent, and between self-reports and informant reports. We conclude that the validity-index approach has good potential for future applications. Future research should further evaluate the approach for different types of questionnaires (e.g., personality inventories) and using different validity indices (e.g., response-bias indices).

First Validation of the Full PROMIS Pain Interference and Pain Behavior Item Banks in Patients With Rheumatoid Arthritis.

OBJECTIVE: Pain interference and pain behavior are highly relevant outcomes in patients with rheumatoid arthritis (RA). The Patient-Reported Outcomes Measurement Information System (PROMIS) is a universally applicable set of item banks measuring patient-reported health, and if applied as computerized adaptive tests (CATs), more efficiently and precisely than current instruments. The objective was to study the psychometric properties of the Dutch-Flemish PROMIS pain interference (PROMIS-PI) and the PROMIS pain behavior (PROMIS-PB) item banks in patients with RA. METHODS: A total of 2,029 patients with RA completed the full PROMIS-PI (version 1.1, 40 items), and 1,554 patients completed the full PROMIS-PB (version 1.1, 39 items). The following psychometric properties were studied: unidimensionality, local dependence, monotonicity and graded response model (GRM) fit, cross-cultural validity (differential item functioning [DIF] for language [Dutch versus Flemish]), other forms of measurement invariance, construct validity, reliability, and floor and ceiling effects. RESULTS: The PROMIS-PI and PROMIS-PB banks were sufficiently unidimensional (Omega-hierarchical [Omega-H] 0.99, 0.95, and explained common variance 0.95, 0.78, respectively), had negligible local dependence (0.3-1.4% of item pairs), good monotonicity (H 0.75, 0.46), and a good GRM model fit (no misfitting items). Furthermore, both item banks showed good cross-cultural validity (no DIF for language), measurement invariance (no DIF for age, sex, administration mode, and disease activity), good construct validity (all hypotheses met), high reliability (>0.90 in the range of patients with RA), and an absence of floor and ceiling effects (0% minimum or maximum score, respectively). CONCLUSION: Both PROMIS-PI and PROMIS-PB banks showed good psychometric properties in patients with RA and can be used as CATs in research and clinical practice.

Synthesis and Structure-Activity Relationships of N-(4-Benzamidino)-Oxazolidinones: Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6.

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high-throughput screen within the European Lead Factory program. Structure-guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)-3-(4-carbamimidoylphenyl)-N-((S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) and 34 ((5R)-3-(6-carbamimidoylpyridin-3-yl)-N-((1S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) have single-digit nanomolar potency against KLK6, with over 25-fold and 100-fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6-dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.