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1.  Linking Pain Items from Two Studies onto a Common Scale using Item Response Theory 
This study examined two approaches to linking items from two pain surveys to form a single item bank with a common measurement scale. Secondary analysis of two independent surveys: IMMPACT Survey with Main Survey (959 chronic pain patients; 42 pain items) and Pain Modules (N=148; 36 pain items); and CORE Survey (400 cancer patients; 43 pain items). There were common items included among the three data sets. The two approaches were examined, one in which all items were calibrated to an item response theory (IRT) model simultaneously and another in which items were calibrated separately and then the scales were transformed to a common metric. The two approaches produced similar linking result across the two sets of pain interference items because there was sufficient number of common items and large enough sample size. For pain intensity, simultaneous calibration yielded more stable results. Separated calibration yielded unsatisfactory linking result for pain intensity because of a single common item with small sample size. The results suggested that simultaneous IRT calibration method produced the more stable item parameters across independent samples, hence, is recommended for developing comprehensive item banks. Patient reported health outcome surveys are often limited in sample sizes and the number of items owing to the difficulty of recruitment and the burden to the patients. As a result, the surveys either lack statistical power or limited in scope. Using IRT methodology, surveys data can be pooled to lend strength to each other to expand the scope and to increase the sample sizes.
PMCID: PMC2761512  PMID: 19577422
item response theory; pain intensity; pain interference; linking studies
2.  The impact of Hunter syndrome (mucopolysaccharidosis type II) on health-related quality of life 
Hunter syndrome (mucopolysaccharidosis type II (MPS II)) is a rare metabolic disease that can severely compromise health, well-being and life expectancy. Little evidence has been published on the impact of MPS II on health-related quality of life (HRQL). The objective of this study was to describe this impact using the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) questionnaire and a range of standard validated questionnaires previously used in paediatric populations.
Clinical and demographic characteristics collected in a clinical trial and responses to four HRQL questionnaires completed both by patients and parents prior to enzyme replacement treatment were used. The association between questionnaire scores and clinical function parameters were tested using Spearman rank-order correlations. Results were compared to scores in other paediatric populations with chronic conditions obtained through a targeted literature search of published studies.
Overall, 96 male patients with MPS II and their parents were enrolled in the trial. All parents completed the questionnaires and 53 patients above 12 years old also completed the self-reported versions. Parents’ and patients’ responses were analysed separately and results were very similar. Dysfunction according to the HS-FOCUS and the CHAQ was most pronounced in the physical function domains. Very low scores were reported in the Self Esteem and Family Cohesion domains in the CHQ and HUI3 disutility values indicated a moderate impact. Scores reported by patients and their parents were consistently lower than scores in the other paediatric populations identified (except the parent-reported Behaviour score); and considerably lower than normative values.
This study describes the impact on HRQL in patients with MPS II and provides a broader context by comparing it with that of other chronic paediatric diseases. Physical function and the ability to perform day-to-day activities were the most affected areas and a considerable impact on the psychological aspects of patients’ HRQL was also found, with a higher level of impairment across most dimensions (particularly Pain and Self Esteem) than that of other paediatric populations. Such humanistic data provide increasingly important support for establishing priorities for health care spending, and as a component of health economic analysis.
PMCID: PMC3722040  PMID: 23837440
Hunter syndrome; Mucopolysaccharidosis type II; Lysosomal storage disease; Patient-reported outcomes; Health-related quality of life
3.  Measuring patient experiences in Fabry disease: validation of the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ) 
Common symptoms for children with Anderson-Fabry Disease (FD) such as acroparaesthesia and gastrointestinal manifestations can only be objectively assessed in patients using a valid instrument. To date, no such instrument exists.
A preliminary 40-item measure of symptoms and experience with FD, the Fabry-specific Paediatric Health and Pain Questionnaire (FPHPQ) was developed, but lacked a formal assessment of its measurement properties. The FPHPQ was used in the Fabry Outcome Survey (FOS), a registry for all patients with a confirmed diagnosis of FD who are receiving agalsidase alfa, or are treatment naïve and who are managed by physicians participating in FOS. After an item analysis to explore how items performed and combined into domains, a battery of psychometric analyses was performed to assess the measurement properties of this new instrument.
Eighty-seven children (ages 4-18 years) completed the questionnaire. Twenty-three items in three subscales of the questionnaire emerged: pain associated with heat or exertion, pain associated with cold, and abdominal pain and fatigue symptoms. Internal consistency reliability for all three subscales was good (Cronbach alpha ≥ 0.84). Reliability was equally high for all age groups (4-7, 8-12, and 13-18). Test-retest reliability was high for all three subscales (intraclass correlation coefficient ≥ 0.74). Construct validity was demonstrated by moderate correlation with brief pain inventory (BPI), KINDL, and EQ-5D. Known group validity showed all subscales were able to discriminate between Fabry disease severity groups as classified by above or below median of the FOS MSSI (Mainz Severity Score Index) grade. The heat or exertion subscale was responsive to change in symptoms between responders and non-responders as defined by change in EQ-5D index scores between the first and second visit.
Preliminary results indicate that the measurement properties of FPHPQ are valid and reliable for assessing patient-reported symptoms of FD. The questionnaire could be a useful tool for clinicians to understand the progression of disease and monitor treatment effects. FPHPQ will be further validated and refined as the FOS registry is continuously adding more patients.
PMCID: PMC3487958  PMID: 22992222
Fabry disease; Enzyme replacement therapy; Children; Paediatric Health and Pain Questionnaire; Psychometrics validation
4.  Content validity and test-retest reliability of patient perception of intensity of urgency scale (PPIUS) for overactive bladder 
BMC Urology  2012;12:26.
The Patient Perception of Intensity of Urgency Scale (PPIUS) is a patient-reported outcome instrument intended to measure the intensity of urgency associated with each urinary or incontinence episode. The objectives of this study were to assess the content validity, test-retest reliability, and acclimation effect of the PPIUS in overactive bladder (OAB) patients.
Patients undergoing treatment for OAB were recruited to participate in a non-interventional study by completing a three-day micturition diary including the PPIUS for three consecutive weeks. Following completion of the three-week study, participants from two select sites also completed a cognitive interview to assess their comprehension of the PPIUS.
Thirty-nine participants successfully completed the three-week test-retest study; twelve of these participants completed the cognitive interview. Test-retest reliability was high based on intra-class correlation coefficient of 0.95. Among stable patients, the difference between the mean ratings of any two weeks was non-significant. Among the twelve interview participants, nine found it simple to choose a PPIUS rating for each of their micturition episodes and most found the urgency rating definitions consistent with their urgency experiences.
The results demonstrated content validity based on qualitative interviews, and excellent test-retest reliability among stable patients. In addition, no acclimation effect was observed among stable patients. These findings support the use of the PPIUS as a reliable measure of urgency in both clinical trial and real life settings. The validity of PPIUS could be further established with future studies investigating the relationship between discretely graded urgency and incontinence continuum.
PMCID: PMC3479079  PMID: 22958621
Over active bladder; OAB; Urinary urgency; Urge incontinence; Patient perception of intensity of urgency scale; PPIUS
5.  Creating scenarios of the impact of copd and their relationship to copd assessment test (CAT™) scores 
The COPD Assessment Test (CAT™) is a new short health status measure for routine use. New questionnaires require reference points so that users can understand the scores; descriptive scenarios are one way of doing this. A novel method of creating scenarios is described.
A Bland and Altman plot showed a consistent relationship between CAT scores and scores obtained with the St George's Respiratory Questionnaire for COPD (SGRQ-C) permitting a direct mapping process between CAT and SGRQ items. The severity associated with each CAT item was calculated using a probabilistic model and expressed in logits (log odds of a patient of given severity affirming that item 50% of the time). Severity estimates for SGRQ-C items in logits were also available, allowing direct comparisons with CAT items. CAT scores were categorised into Low, Medium, High and Very High Impact. SGRQ items of corresponding severity were used to create scenarios associated with each category.
Each CAT category was associated with a scenario comprising 12 to 16 SGRQ-C items. A severity 'ladder' associating CAT scores with exemplar health status effects was also created. Items associated with 'Low' and 'Medium' Impact appeared to be subjectively quite severe in terms of their effect on daily life.
These scenarios provide users of the CAT with a good sense of the health impact associated with different scores. More generally they provide a surprising insight into the severity of the effects of COPD, even in patients with apparently mild-moderate health status impact.
PMCID: PMC3199910  PMID: 21835018
6.  The Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) Questionnaire: item reduction and further validation 
Quality of Life Research  2014;23(9):2457-2462.
The Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) Questionnaire is a patient and parent-completed disease-specific instrument used in Hunter syndrome (mucopolysaccharidosis II), a rare paediatric progressive multi-systemic lysosomal storage disease. The objective of this study was to shorten the number of items of the Questionnaire to reduce response burden while maintaining its content validity.
Data collected in a clinical trial were used. An iterative process helped identifying redundant or low performing items based on content validity and psychometric properties. Validation on the retained items was assessed using patients and parent’s responses in terms of reliability, validity and responsiveness.
The HS-FOCUS was completed by 49 patients and 84 parents. Items were mainly removed owing to high floor effects, high inter-item correlations (>0.80) or inadequate content. The shortened patient and parent versions (18 and 21 items) each contained five function domains. Internal consistency and test–retest reliability were >0.70 for most domains, except Breathing and School/work. Concurrent validity was demonstrated by significant correlations (>0.30) with similar concepts of previously validated measures. Significant differences were found in all domain scores across levels of disability.
The shortened HS-FOCUS is a reliable, valid and responsive measure, where burden in answering the Questionnaire was reduced without compromising its validity.
PMCID: PMC4186975  PMID: 24806354
Hunter syndrome; Mucopolysaccharidosis type II; Lysosomal storage disease; Patient-reported outcomes; Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS)
7.  Item selection, reliability and validity of the Shortness of Breath with Daily Activities (SOBDA) questionnaire: a new outcome measure for evaluating dyspnea in chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is characterized by irreversible, progressive obstruction of lung airflow. Dyspnea (shortness of breath [SOB]) is the COPD symptom which most negatively impacts patients’ daily activities. To assess how SOB affects daily activities, 37 items were drafted through focus group discussions and cognitive interviews with COPD patients to develop a patient-reported outcome instrument: the Shortness of Breath with Daily Activities questionnaire (SOBDA). Psychometric analysis was conducted to reduce the number of items and evaluate the measurement properties of the final SOBDA.
Prospective, observational study of 334 COPD patients, recruited from 24 pulmonology and internal medicine clinics in the United States. The 37-item SOBDA was administered to patients each evening for 28 days using an electronic diary. Patients answered every item and rated their level of SOB experienced that day during specific activities. Item selection was conducted by examining item characteristics, dimensionality, and Rasch model analysis results. The decision to delete an item was based on psychometric evidence, content validity, and expert clinical input. The final SOBDA instrument was evaluated for internal consistency, reproducibility, convergent validity, known-groups validity, and responsiveness.
Twenty-four items from the 37-item pool were removed following the item selection process: nine items were removed due to high item-to-item correlations; five due to floor effects; three due to infrequent activity; one due to gender bias; two due to low factor loadings; three due to unordered response options; and one due to expert’s discretion. Internal consistency and reproducibility of the final SOBDA were demonstrated by Cronbach Alpha = 0.87, and intra-class correlation coefficient = 0.91. Convergent validity was demonstrated by high correlation with the CRQ-SAS (0.60) and SGRQ-C (0.61). Known groups validity was demonstrated by significant difference between ratings of the mMRC and clinical global rating of severity. Evaluation of the ability to detect change was not performed owing to too few responders at the end of the study.
Through the empirical item reduction process, 13 items were selected from the 37-item pool generated during qualitative development. The final 13-item SOBDA is a reliable and valid instrument for use in clinical trials.
PMCID: PMC3835406  PMID: 24229361
Chronic obstructive pulmonary disease; Dyspnea; Shortness of breath; Patient-reported outcome measure; Shortness of breath with daily activities questionnaire
8.  Shortness of Breath with Daily Activities questionnaire: validation and responder thresholds in patients with chronic obstructive pulmonary disease 
BMJ Open  2013;3(10):e003048.
To test the reliability, validity and responsiveness of the 13-item Shortness of Breath with Daily Activities (SOBDA) questionnaire, and determine the threshold for response and minimal important difference (MID).
6 week, randomised, double-blind, placebo-controlled study.
40 centres in the USA between 29 October 2009 and 1 July 2010.
Primary and secondary outcome measures
547 patients with chronic obstructive pulmonary disease (COPD) were enrolled and 418 entered the 2-week run-in period. Data from the run-in period were collected to test internal consistency, test–retest reliability, convergent validity and known-groups validity of the SOBDA. Three hundred and sixty six patients were randomised 2:2:1 to fluticasone propionate/salmeterol 250/50 µg, salmeterol 50 µg or placebo, twice daily. Results from the SOBDA questionnaire, Patient Global Assessment of Change Question, modified Medical Research Council Dyspnoea Scale (mMRC), Clinician Global Impression of Dysponea Severity (CGI-S), Clinician Global Impression of Change Question and Chronic Respiratory Disease Questionnaire self-administered standardised version (CRQ-SAS) were evaluated; spirometry and safety parameters were measured. Study endpoints were selected to investigate the cross-sectional and longitudinal validity of the SOBDA questionnaire in relation to the clinical criteria.
Internal consistency of the SOBDA questionnaire (Cronbach α) was 0.89. Test–retest reliability (intraclass correlation) was 0.94. The SOBDA weekly scores correlated with the patient-reported and clinician-reported mMRC, CGI-S and CRQ-SAS dyspnoea domain scores (0.29, 0.24, 0.24 and –0.68, respectively). The SOBDA weekly scores differentiated between the responders and the non-responders as rated by the patients and the clinicians. Anchor-based and supportive distribution-based analyses produced a range of the potential values for the threshold for the responders and MID.
The 13-item SOBDA questionnaire is reliable, valid and responsive to change in patients with COPD. On using anchor-based methods, the proposed responder threshold shows a −0.1 to −0.2 score change. A specific threshold value will be identified as more data are generated from future clinical trials.
Trial registration
NCT00984659; GlaxoSmithKline study number: ASQ112989.
PMCID: PMC3808824  PMID: 24154513
9.  Purification, crystallization and preliminary X-ray analysis of a thermostable direct haemolysin from Grimontia hollisae  
The thermostable direct haemolysin from G. hollisae has been purified and crystallized in two crystal forms using the vapour-diffusion method.
Vibrio hollisae, a halophilic species recently reclassified as Grimontia hollisae, is a causative agent of gastroenteritis and septicaemia. One important pathogenic Vibrio factor, thermostable direct haemolysin (TDH), has been purified and crystallized in two crystal forms using the vapour-diffusion method. The crystals belonged to an orthorhombic space group, with unit-cell parameters a = 104.8, b = 112.4, c = 61.3 Å and a = 122.9, b = 123.3, c = 89.8 Å. The crystals contained either four or eight molecules per asymmetric unit, with predicted solvent contents of 49.4 and 46.3% and Matthews coefficients (V M) of 2.4 and 2.3 Å3 Da−1, respectively. These crystals were suitable for structure determination, which would yield structural details related to the cytotoxicity and oligomeric structure of this pore-forming toxin.
PMCID: PMC3034613  PMID: 21301091
thermostable direct haemolysin; Grimontia hollisae
10.  Development of A Promis Item Bank to Measure Pain Interference 
Pain  2010;150(1):173-182.
This paper describes the psychometric properties of the PROMIS Pain Interference (PROMIS-PI) bank. An initial candidate item pool (n=644) was developed and evaluated based on review of existing instruments, interviews with patients, and consultation with pain experts. From this pool, a candidate item bank of 56 items was selected and responses to the items were collected from large community and clinical samples. A total of 14,848 participants responded to all or a subset of candidate items. The responses were calibrated using an item response theory (IRT) model. A final 41-item bank was evaluated with respect to IRT assumptions, model fit, differential item function (DIF), precision, and construct and concurrent validity. Items of the revised bank had good fit to the IRT model (CFI and NNFI/TLI ranged from 0.974 to 0.997), and the data were strongly unidimensional (e.g., ratio of first and second eigenvalue = 35). Nine items exhibited statistically significant DIF. However, adjusting for DIF had little practical impact on score estimates and the items were retained without modifying scoring. Scores provided substantial information across levels of pain; for scores in the T-score range 50-80, the reliability was equivalent to 0.96 to 0.99. Patterns of correlations with other health outcomes supported the construct validity of the item bank. The scores discriminated among persons with different numbers of chronic conditions, disabling conditions, levels of self-reported health, and pain intensity (p< 0.0001). The results indicated that the PROMIS-PI items constitute a psychometrically sound bank. Computerized adaptive testing and short forms are available.
PMCID: PMC2916053  PMID: 20554116
Quality-of-life outcomes; quality-of-life measurement; pain
11.  Site-Directed Mutations of Thermostable Direct Hemolysin from Grimontia hollisae Alter Its Arrhenius Effect and Biophysical Properties 
Recombinant thermostable direct hemolysin from Grimontia hollisae (Gh-rTDH) exhibits paradoxical Arrhenius effect, where the hemolytic activity is inactivated by heating at 60 oC but is reactivated by additional heating above 80 oC. This study investigated individual or collective mutational effect of Tyr53, Thr59, and Ser63 positions of Gh-rTDH on hemolytic activity, Arrhenius effect, and biophysical properties. In contrast to the Gh-rTDH wild-type (Gh-rTDHWT) protein, a 2-fold decrease of hemolytic activity and alteration of Arrhenius effect could be detected from the Gh-rTDHY53H/T59I and Gh-rTDHT59I/S63T double-mutants and the Gh-rTDHY53H/T59I/S63T triple-mutant. Differential scanning calorimetry results showed that the Arrhenius effect-loss and -retaining mutants consistently exhibited higher and lower endothermic transition temperatures, respectively, than that of the Gh-rTDHWT. Circular dichroism measurements of Gh-rTDHWT and Gh-rTDHmut showed a conspicuous change from a β-sheet to α-helix structure around the endothermic transition temperature. Consistent with the observation is the conformational change of the proteins from native globular form into fibrillar form, as determined by Congo red experiments and transmission electron microscopy.
PMCID: PMC3076507  PMID: 21494434
Grimontia hollisae; thermostable direct hemolysin; Arrhenius effect; Circular Dichroism; virulence factor
12.  Development and Psychometric Analysis of the PROMIS Pain Behavior Item Bank 
Pain  2009;146(1-2):158-169.
The measurement of pain behavior is a key component of the assessment of persons with chronic pain; however few self-reported pain behavior instruments have been developed. We developed a pain behavior item bank as part of the Patient Reported Outcome Measurement Information System (PROMIS). For the Wave I testing, because of the large number of PROMIS items, a complex sampling approach was used where participants were randomly assigned to either respond to two full item banks or to multiple 7-item blocks of items. A web-based survey was designed and completed by 15,528 members of the general population and 967 individuals with different types of chronic pain. Item response theory (IRT) analysis models were used to evaluate item characteristics and to scale both items and individuals on the pain behavior domain. The pain behavior item bank demonstrated good fit to a unidimensional model (Comparative Fit Index = 0.94). Several iterations of IRT analyses resulted in a final 39 item pain behavior bank, and different IRT models were fit to the total sample and to those participants who experienced some pain. The results indicated that these items demonstrated good coverage of the pain behavior construct. Pain behavior scores were strongly related to pain intensity and moderately related to self-reported general health status. Mean pain behavior scores varied significantly by groups based on pain severity and general health status. The PROMIS pain behavior item bank can be used to develop static short-form and dynamic measures of pain behavior for clinical studies.
PMCID: PMC2775487  PMID: 19683873
Pain behavior; item response theory analysis; patient reported outcomes; psychometric analysis; chronic pain; item banks
13.  Predicting EuroQol (EQ-5D) scores from the patient-reported outcomes measurement information system (PROMIS) global items and domain item banks in a United States sample 
Quality of Life Research  2009;18(6):783-791.
Preference-based health index scores provide a single summary score assessing overall health-related quality of life and are useful as an outcome measure in clinical studies, for estimating quality-adjusted life years for economic evaluations, and for monitoring the health of populations. We predicted EuroQoL (EQ-5D) index scores from patient-reported outcomes measurement information system (PROMIS) global items and domain item banks.
This was a secondary analysis of health outcome data collected in an internet survey as part of the PROMIS Wave 1 field testing. For this study, we included the 10 global items and the physical function, fatigue, pain impact, anxiety, and depression item banks. Linear regression analyses were used to predict EQ-5D index scores based on the global items and selected domain banks.
The regression models using eight of the PROMIS global items (quality of life, physical activities, mental health, emotional problems, social activities, pain, and fatigue and either general health or physical health items) explained 65% of the variance in the EQ-5D. When the PROMIS domain scores were included in a regression model, 57% of the variance was explained in EQ-5D scores. Comparisons of predicted to actual EQ-5D scores by age and gender groups showed that they were similar.
EQ-5D preference scores can be predicted accurately from either the PROMIS global items or selected domain banks. Application of the derived regression model allows the estimation of health preference scores from the PROMIS health measures for use in economic evaluations.
PMCID: PMC2704290  PMID: 19472072
Health preference scores; EQ-5D; PROMIS; Global health status; Health-related quality of life

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