Traceability and comparability through crosswalks with the NeuroMET Memory Metric.

Accurate assessment of memory ability for persons on the continuum of Alzheimer's disease (AD) is vital for early diagnosis, monitoring of disease progression and evaluation of new therapies. However, currently available neuropsychological tests suffer from a lack of standardization and metrological quality assurance. Improved metrics of memory can be created by carefully combining selected items from legacy short-term memory tests, whilst at the same time retaining validity, and reducing patient burden. In psychometrics, this is known as "crosswalks" to link items empirically. The aim of this paper is to link items from different types of memory tests. Memory test data were collected from the European EMPIR NeuroMET and the SmartAge studies recruited at Charité Hospital (Healthy controls n = 92; Subjective cognitive decline n = 160; Mild cognitive impairment n = 50; and AD n = 58; age range 55-87). A bank of items (n = 57) was developed based on legacy short-term memory items (i.e., Corsi Block Test, Digit Span Test, Rey's Auditory Verbal Learning Test, Word Learning Lists from the CERAD test battery and Mini Mental State Examination; MMSE). The NeuroMET Memory Metric (NMM) is a composite metric that comprises 57 dichotomous items (right/wrong). We previously reported on a preliminary item bank to assess memory based on immediate recall, and have now demonstrated direct comparability of measurements generated from the different legacy tests. We created crosswalks between the NMM and the legacy tests and between the NMM and the full MMSE using Rasch analysis (RUMM2030) and produced two conversion tables. Measurement uncertainties for estimates of person memory ability with the NMM across the full span were smaller than all individual legacy tests, which demonstrates the added value of the NMM. Comparisons with one (MMSE) of the legacy tests showed however higher measurement uncertainties of the NMM for people with a very low memory ability (raw score ≤ 19). The conversion tables developed through crosswalks in this paper provide clinicians and researchers with a practical tool to: (i) compensate for ordinality in raw scores, (ii) ensure traceability to make reliable and valid comparisons when measuring person ability, and (iii) enable comparability between test results from different legacy tests.

Proxy reporting of health-related quality of life for people with dementia: a psychometric solution.

BACKGROUND: The growing move towards personalised health and social care systems means that every effort needs to be made to generate patient-reported outcome data. However, the deteriorating nature of dementia can make it difficult for people with dementia to complete self-reported questionnaires and it is often necessary to rely on a family member (proxy) to report on their behalf. There is little evidence to guide how the difference between self- and proxy-reports of health reported quality of life (HRQL) in dementia can be interpreted. METHODS: We recruited people with dementia and their family carers from 78 memory Assessment Services in the UK. We used Rasch measurement methods to investigate whether a HRQL questionnaire known as DEMQOL (self-reported by the person with dementia) and DEMQOL-Proxy (proxy-reported by a family carer) can be placed on the same continuum and whether a revised scoring algorithm, based on this equated model, can be developed that takes account of the relationship between self- and proxy-reports. RESULTS: In a sample of 1434 patients and 1030 carers, our findings supported equating DEMQOL/DEMQOL-Proxy (overall fit to the model; no mis-fitting items) after addressing specific issues (eight disordered items requiring re-scoring, four pairs locally dependent items, and five items showing DIF). Cross walk tables have been produced. CONCLUSIONS: We have established for the first time that DEMQOL and DEMQOL-Proxy can be placed on the same continuum and that patients and carer proxies are reporting on the same construct when they complete these questionnaires. Where possible both DEMQOL and DEMQOL-Proxy should still be administered together, using the improved scoring algorithm reported here. Where only DEMQOL-Proxy is available, the cross walk tables provide an estimate of DEMQOL for a particular person from their DEMQOL-Proxy score.

Development of a new patient-reported outcome measure to evaluate treatments for acne and acne scarring: the ACNE-Q.

BACKGROUND: Psychosocial concerns represent important outcomes in studies of treatments for acne and acne scarring. Also important, but largely overlooked, is the concept of appearance. OBJECTIVES: To design an acne-specific patient-reported outcome measure for acne and acne scarring. METHODS: We used a mixed-methods approach. Phase I involved 21 patient interviews that were audio-recorded, transcribed and coded. Concepts were identified and developed into scales that were refined through 10 cognitive interviews and input from 16 clinical experts. Phase II involved data collection at hospital and community-based dermatology clinics in Canada and the U.S.A. Eligible participants were aged 12 years and older with acne and/or acne scars on the face, chest and/or back. Rasch Measurement Theory (RMT) analyses were performed to examine psychometric properties. RESULTS: Phase I led to the development of seven scales that measure appearance of facial skin, acne (face, chest and back) and acne scars, acne-specific symptoms and appearance-related distress. In phase II, 256 patients completed the ACNE-Q. RMT analysis provided evidence that the items of each scale worked together conceptually and statistically. Most participants scored within the range of measurement for each scale (81·9-93·1%). Reliability was high, with person separation index values and Cronbach alpha values > 0·90 for the appearance scales, ≥ 0·87 for appearance-related distress and ≥ 0·75 for symptoms. Worse scores on appearance scales correlated with worse symptom scores and more appearance-related distress. CONCLUSIONS: The ACNE-Q is a rigorously developed instrument that can be used to measure appearance and other patient-centred concerns. What's already known about this topic? Acne is a common dermatological condition that can have an important impact on psychosocial function. Current patient-reported outcome measures specific to acne focus mostly on measuring psychological and social impact. What does this study add? The ACNE-Q provides a set of independently functioning scales that measure appearance of facial, back and chest acne, acne scarring and facial skin. Additional scales measure appearance-related distress and acne symptoms. What are the clinical implications of this work? ACNE-Q provides the dermatology community with a rigorously developed patient-reported measure for acne that can be applied in clinical trials, research and patient care. The measurement of appearance by ACNE-Q scales is more comprehensive than in other instruments providing important information on appearance of their acne and/or acne scars from the patient perspective.

FACE-Q Skin Cancer Module for measuring patient-reported outcomes following facial skin cancer surgery.

BACKGROUND: The patient's perspective of their facial scar after skin cancer surgery influences perception of care and quality of life (QoL). Appearance satisfaction after surgery is also an important but often overlooked treatment outcome. OBJECTIVES: To report the psychometric validation of the FACE-Q Skin Cancer Module consisting of five scales, measuring appearance satisfaction (Satisfaction with Facial Appearance, Appraisal of Scars), QoL (Cancer Worry, Appearance-related Psychosocial Distress) and the patient experience (Satisfaction with Information: Appearance). METHODS: Participants underwent Mohs surgery for facial basal or squamous cell carcinoma or excision of early facial melanoma. Cohort 1 received a set of scales before and after surgery. Cohort 2 received the scales on two occasions in the postoperative period for test-retest reliability. Rasch measurement theory was used to select (item-reduce) the most clinically meaningful items for the scales. Reliability, validity, floor and ceiling effects and responsiveness were also analysed. RESULTS: Of 334 patients, 209 (response rate 62·6%) were included. Rasch analysis reduced the total scale items from 77 to 41. All items had ordered thresholds and good psychometric fit. Reliability was high (Person separation index and Cronbach's α ≥ 0·90) and scales measuring similar constructs were correlated. High floor and ceiling effects were seen for the scales. The Cancer Worry scale demonstrated responsiveness (P = 0·004). CONCLUSIONS: The FACE-Q Skin Cancer Module meet the requirements of the Rasch model providing linearized measurement. Discriminating between patients with minimal appearance or worry impairment may be a limitation. The scales can be used for larger validation studies, clinical practice and research.

Development and validation of a generic scale for use in transition programmes to measure self-management skills in adolescents with chronic health conditions: the TRANSITION-Q.

AIM: To develop a generic self-management skills scale for use with adolescents diagnosed with a chronic health condition who are aged 12 to 18 years. BACKGROUND: There is a lack of methodologically sound scales for healthcare teams to use to measure self-management skills in adolescents with chronic conditions transitioning to adult care. METHODS: Adolescents aged 12 to 18 years with a broad range of chronic health conditions, including neurodevelopmental conditions, were recruited from May to August 2013 from nine outpatient clinics at McMaster Children's Hospital (Canada). Thirty-two participated in a cognitive interview, and 337 completed a questionnaire booklet. Interviews were used to develop the TRANSITION-Q. Rasch measurement theory (RMT) analysis was used to identify items that represent the best indicators of self-management skills. Traditional psychometric tests of measurement performance were also conducted. RESULTS: The response rate was 92% (32/32 cognitive; 337/371 field test). RMT analysis resulted in a 14-item scale with three response options. The overall fit of the observed data to that expected by the Rasch model was non-significant, providing support that this new scale measured a unidimensional construct. Other tests supported the scale as scientifically sound, e.g. Person Separation Index = 0.82; good item fit statistics; no differential item function by age or gender; low residual correlations between items; Cronbach's alpha = 0.85; test-retest reliability = 0.90; and tests of construct validity that showed, as hypothesized, fewer skills in younger participants and in participants who required assistance to complete the scale. Finally, participants who agreed they are ready to transfer to adult healthcare reported higher TRANSITION-Q scores than did participants who disagreed. CONCLUSIONS: The TRANSITION-Q is a short, clinically meaningful and psychometrically sound scale. This generic scale can be used in research and in paediatric and adolescent clinics to help evaluate readiness for transition.

What constitutes uncertainty in systemic lupus erythematosus and rheumatoid arthritis?

Patient uncertainty is associated with conditions with no known cause or cure, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and despite its potential role in chronic illness management, it is still a poorly understood concept. This study constitutes an in-depth investigation of patient uncertainty in SLE and RA. We conducted (i) structured interviews with a sample of rheumatology health care professionals (HCPs) (n = 8) and (ii) in-depth, semi-structured interviews with a sample of SLE (n = 17) and RA (n = 15) patients. Interviews were audio-taped, transcribed verbatim and analysed thematically using detailed line-by-line coding. Patient uncertainty was conceptualised in a framework of five domains: symptoms and prognosis, medical management, self-management, impact and social functioning. Even though these five domains were present in both the SLE and RA data, there were some differences at the sub-domain level. Several sources of uncertainty were put forward by the HCPs and subsequently confirmed in the patient interviews including the illness trajectory, age, gender and timing. Patients reported uncertainty relative to various aspects of their illness, its management and impact. Finally, HCPs discussed the behavioural and psychosocial impact of uncertainty, which further suggests its important role in patient management.

Can the ABILHAND handle manual ability in MS?

BACKGROUND: Hand dysfunction is common in multiple sclerosis (MS). Recent interest has focused on incorporating patient-reported outcome (PRO) instruments into clinical trials. Nevertheless, examinations are rare in MS of existing manual ability measures. OBJECTIVES: The objective of this paper is to evaluate the 23-item ABILHAND, developed for use after stroke, in people with MS, comparing the findings from two psychometric approaches. METHODS: We analysed ABILHAND data from 300 people with MS using: 1) traditional psychometric methods (data completeness, scaling assumptions, reliability, internal and external construct validity); and 2) Rasch measurement methods (including targeting, item response category ordering, data fit to the Rasch model, spread of item locations, item scoring bias, item stability, reliability, person response validity). RESULTS: Traditional psychometric methods implied ABILHAND was reliable and valid in this sample. Rasch measurement methods supported this finding. The three-category scoring function worked as intended and item fit to Rasch model expectations was acceptable. The 23 items (location range -3.16 to +2.73 logits) mapped a continuum of manual ability. Reliability was high (Person Separation Index (PSI) = 0.95). CONCLUSION: Both psychometric evaluations supported ABILHAND as a robust manual ability PRO measure for MS. Rasch measurement methods were more informative and, consistent with its role of detecting anomalies, identified ways of advancing further ABILHAND's measurement performance to reduce any potential for type II errors in clinical trials.

Beyond the reach of traditional analyses: using Rasch to evaluate the DASH in people with multiple sclerosis.

BACKGROUND: Few upper limb functioning patient rating scales have been used in multiple sclerosis (MS) research and none developed specifically for people with MS. OBJECTIVES: In this study, we examined the Disabilities of the Arm, Shoulder and Hand (DASH) to determine its utility as a useful, scientifically robust and clinically meaningful tool in MS. METHODS: DASH data from 300 people with MS underwent two independent phases of psychometric analyses: (1) a traditional psychometric analysis (including data quality, scaling assumptions, reliability and validity); and (2) a Rasch analysis (including response option thresholds ordering, tests of fit, spread of item locations, residual correlations, and person separation index). RESULTS: Overall, the traditional psychometric analysis supported the DASH as a reliable and valid measure of upper limb function in people with MS. However, several issues were raised by the Rasch analysis that questioned the validity of the DASH, including misfit in 13/30 items, disordered item response option thresholds for 9/30 items, and six pairs of items with high residual correlations (> 0.60). CONCLUSION: Rasch analysis highlights areas for potential improvement for the use of the DASH. Our findings further support our previous arguments that traditional psychometric methods provide weak scale evaluations and can mislead clinicians as to the reliability and validity of outcome measures.

Evaluating family-centred service in paediatric oncology with the measure of processes of care (MPOC-20).

BACKGROUND: In order to evaluate the family-centeredness of paediatric oncology services, a psychometrically sound measure of family-centred services is needed. We performed a comprehensive evaluation of the psychometric properties of the 20-item Measure of Processes of Care (MPOC-20) in parents of children undergoing treatment for cancer at five paediatric oncology centres in Canada. METHODS: The sample included 411 parents (80% response rate). Exploratory factor analysis was used to determine the best way to group the items into scales. Psychometric tests were used to examine data quality, targeting, internal consistency reliability, within-scale construct validity and known-groups validity. RESULTS: Exploratory factor analysis identified two factors: a summary measure of family-centred services and a scale measuring activities that meet parents' general informational needs. Scores spanned the entire scale range, floor and ceiling effects were low, and the sample distribution was not unduly skewed. Scales showed acceptable internal consistency reliability (Cronbach's alphas > or =0.93). Known-group hypotheses supported the scales' ability to differentiate between groups hypothesized to differ. Moderate effect sizes were found when MPOC-20 scale scores for parents and for children with good quality of life were compared with those with poor quality of life. CONCLUSIONS: The MPOC-20 is the only evaluated instrument currently available to measure family-centred services in paediatric oncology. Paediatric cancer programmes can now use this tool to determine parental perception of the extent to which services are family-centred.

General morphological and biological features of neoplasms: integration of molecular findings.

This review highlights the importance of morphology-molecular correlations for a proper implementation of new markers. It covers both general aspects of tumorigenesis (which are normally omitted in papers analysing molecular pathways) and the general mechanisms for the acquired capabilities of neoplasms. The mechanisms are also supported by appropriate diagrams for each acquired capability that include overlooked features such as mobilization of cellular resources and changes in chromatin, transcription and epigenetics; fully accepted oncogenes and tumour suppressor genes are highlighted, while the pathways are also presented as activating or inactivating with appropriate colour coding. Finally, the concepts and mechanisms presented enable us to understand the basic requirements for the appropriate implementation of molecular tests in clinical practice. In summary, the basic findings are presented to serve as a bridge to clinical applications. The current definition of neoplasm is descriptive and difficult to apply routinely. Biologically, neoplasms develop through acquisition of capabilities that involve tumour cell aspects and modified microenvironment interactions, resulting in unrestricted growth due to a stepwise accumulation of cooperative genetic alterations that affect key molecular pathways. The correlation of these molecular aspects with morphological changes is essential for better understanding of essential concepts as early neoplasms/precancerous lesions, progression/dedifferentiation, and intratumour heterogeneity. The acquired capabilities include self-maintained replication (cell cycle dysregulation), extended cell survival (cell cycle arrest, apoptosis dysregulation, and replicative lifespan), genetic instability (chromosomal and microsatellite), changes of chromatin, transcription and epigenetics, mobilization of cellular resources, and modified microenvironment interactions (tumour cells, stromal cells, extracellular, endothelium). The acquired capabilities defining neoplasms are the hallmarks of cancer, but they also comprise useful tools to improve diagnosis and prognosis, as well as potential therapeutic targets. The application of these concepts in oncological pathology leads to consideration of the molecular test requirements (Molecular Test Score System) for reliable implementation; these requirements should cover biological effects, molecular pathway, biological validation, and technical validation. Sensible application of molecular markers in tumour pathology always needs solid morphological support.

Trichilemmal carcinoma with neuroendocrine differentiation.

We report a 12-mm nodular, cream-coloured skin lesion that appeared on the left nasal ala in an 81-year-old man. This trabecular infiltrative tumour showed keratin microcysts, stromal hyalization, cytoarchitectural malignancy features, colonizing melanocytes, and immunoexpression of epithelial membrane antigen, cytokeratin 15/20, chromogranin, synaptophysin and CD56. To our knowledge, this is the first documented case of a trichilemmal carcinoma with neuroendocrine differentiation and melanocyte colonization, which is suggested by the trabecular growth pattern and requires immunohistochemical confirmation. The colonization of the epithelial nests by nonatypical dendritic or spindle melanocytes is a clue to morphological recognition of pilar neoplasms, along with the presence of stromal induction (CD34-positive peritumoral spindle cells), catagen-like apoptotic bodies, calcifications, keratin microcysts and cell balls.

Microsatellite abnormalities and somatic down-regulation of mismatch repair characterize nodular-trabecular muscle-invasive urothelial carcinoma of the bladder.

AIMS: To correlate histological infiltration patterns with genetic and mismatch repair (MMR) profiles in muscle-invasive bladder urothelial carcinomas (UroC). METHODS AND RESULTS: Infiltration patterns were assessed in the deep compartment of muscle-invasive UroC (nodular-trabecular, 45 cases; infiltrative, 27 cases). Tumour compartment (superficial and deep to muscularis mucosa) analysis included: microsatellite pattern of TP53, RB1, WT1 and NF1 by polymerase chain reaction/denaturing gradient gel electrophoresis; mitotic, Ki67, in situ end labelling (ISEL) indices and DNA ploidy. MMR was assessed by MLH1 and MSH2 sequencing and immunohistochemistry in UroC with two or more abnormal microsatellite loci. Statistical differences were tested using anova and Fisher's exact tests. Infiltrative UroC showed lower Ki67 index 14.94 +/- 4.28, ISEL index 14.1 +/- 10.0 and shorter median survival (20 months) than nodular-trabecular UroC (Ki67 index 20.65 +/- 4.94, ISEL 20.2 +/- 22.7, 37-month survival, respectively). The genetic profile was significantly different for RB1 (P = 0.0003) and NF1 (P = 0.0023) only, being more frequently abnormal in nodular-trabecular UroC. A significant decrease in MLH1 or MSH2 protein expression with no gene mutations was identified in UroC with microsatellite abnormalities and a nodular-trabecular growth pattern. CONCLUSIONS: Somatic down-regulation of MMR proteins in nodular-trabecular muscle-invasive UroC results in RB1/NF1 microsatellite abnormalities, correlating with higher cellular turnover and longer survival.

Differential kinetic features by tumour topography in cutaneous small-cell neuroendocrine (Merkel cell) carcinomas.

BACKGROUND/OBJECTIVES: Merkel cell carcinomas (MCC) reveal epithelial and neuroendocrine differentiation, but its topographic cell kinetics remains unknown. This study analyses proliferation, apoptosis, and DNA ploidy by topography, features that can help planning therapeutic protocols. This study topographically analyses proliferation, apoptosis, and DNA ploidy. METHODS: We selected 27 small-cell MCCs (expressing one epithelial and two neural markers, with consistent ultrastructural findings) to evaluate mitotic figure counting, Ki-67 index, apoptosis index based on the in situ end labelling of fragmented DNA (using Escherichia coli DNA polymerase I, Klenow fragment), DNA ploidy, and BCL2 and TP53 immuno-expression. At least 50 high-power fields were screened per topographic compartment (superficial or papillary dermis, and deep or reticular dermis), recording average and standard deviation for each variable. Variables were statistically compared in each tumour compartment using analysis of variance and Student's t-test (significant if P < 0.05). RESULTS: MCCs revealed superficial aneuploid DNA content, and no topographic differences for proliferation markers. Apoptosis showed significantly lower values in the deep compartment (average, P = 0.0050, and standard deviation, P = 0.0074), correlating with increased BCL2 and TP53 immuno-expressions. CONCLUSIONS: High homogeneously distributed proliferation and superficial aneuploid DNA content defines MCCs. Apoptosis follows proliferation in superficial compartments, being less variable and proliferation independent in deep compartments, where it is inversely correlated with BCL2/TP53 expression.

Vocational rehabilitation services for people with multiple sclerosis: what patients want from clinicians and employers.

BACKGROUND: The NSF for Long-term Neurological Conditions highlights the need for vocational rehabilitation services. Although the barriers to work for people with MS (pwMS) have been clearly identified, there has been little research that identifies the type of support required. OBJECTIVE: To identify what pwMS require from a vocational rehabilitation service in terms of content and service delivery. DESIGN OF STUDY: Four focus groups of pwMS, currently in employment, were convened. These were audio-taped and content analysed using a constant comparison method. RESULTS: People with MS identified two key needs; managing performance and managing expectations. Performance difficulties could be managed either by treating symptoms, by changing the environment, or by altering the demands of the job. PwMS highlighted the need for counselling to help them, and advocacy to help their employers have appropriate expectations. CONCLUSION: PwMS need support in the workplace in two distinct ways. First, by managing the interaction between the impairments caused by MS, the physical environment, and the demands imposed by the work. Second, by providing expert knowledge about the employment environment and the needs of employers, an awareness of the relevant legislation and counselling in supporting people to adapt, adjust and resolve complex issues.

Cytoarchitectural and kinetic features in the histological evaluation of follicular thyroid neoplasms.

AIMS: The diagnosis of follicular thyroid carcinomas is mainly based on capsular and vascular invasion. The aim of this study was to determine the diagnostic relevance of nuclear features, inflammation and stromal changes. METHODS AND RESULTS: Anisokaryosis, chromatin pattern, nucleolus, nuclear pleomorphism, nuclear/cytoplasmic ratio, necrosis, stromal changes and tumour interstitial lymphocytes (TIL) were analysed in adenomatous hyperplastic nodules (39), adenomas (43) and carcinomas (28 minimally invasive, 48 widely invasive and 27 anaplastic). Ki67 immunostaining, in situ end labelling (ISEL) for apoptosis and the Ki67/ISEL index were analysed by topographical compartments. Variables were compared by histological diagnosis using Fisher's exact test, analysis of variance and Student's t-tests and considered significant if P < 0.05. TIL were absent in 96% of neoplasms and 54% of adenomatous hyperplastic nodules. Conspicuous nucleoli, increased nuclear-cytoplasmic ratio and coexistent apoptosis-myxoid changes distinguished minimally invasive carcinomas from adenomas. The most specific variables of high-grade carcinoma were vasculonecrotic patterns, nuclear hyperchromatism and pleomorphism. A kinetic advantage predominated in the internal compartments of benign lesions and in the peripheral compartments of malignant lesions. CONCLUSIONS: Follicular carcinomas show up-regulation of proliferation markers and the distinctive topographical kinetic profiles provide a basis for the distinction between benign and malignant and an explanation for the circumscription and encapsulation of benign lesions.

CDIP-58 can measure the impact of botulinum toxin treatment in cervical dystonia.

We compared the responsiveness of the Cervical Dystonia Impact Profile (CDIP-58), Medical Outcome Study Short Form-Health Survey (SF-36), Functional Disability Questionnaire (FDQ), and Pain and Activities of Daily Living subscales of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) in participants with cervical dystonia treated with botulinum toxin A. Subscales of CDIP-58 were more sensitive in detecting statistical and clinical change than comparable subscales of the SF-36, FDQ, and TWSTRS.