Minimally important change determined by a visual method integrating an anchor-based and a distribution-based approach

Background: Minimally important changes (MIC) in scores help interpret results from health status instruments. Various distribution-based and anchor-based approaches have been proposed to assess MIC. Objectives: To describe and apply a visual method, called the anchor-based MIC distribution method, which integrates both approaches. Method: Using an anchor, patients are categorized as persons with an important improvement, an important deterioration, or without important change. For these three groups the distribution of the change scores on the health status instrument are depicted in a graph. We present two cut-off points for an MIC: the ROC cut-off point and the 95% limit cut-off point. Results: We illustrate our anchor-based MIC distribution method determining the MIC for the Pain Intensity Numerical Rating Scale in patients with low back pain, using two conceivable definitions of minimal important change on the anchor. The graph shows the distribution of the scores of the health status instrument for the relevant categories on the anchor, and also the consequences of choosing the ROC cut-off point or the 95% limit cut-off point. Discussion: The anchor-based MIC distribution method provides a general framework, applicable to all kind of anchors. This method forces researchers to choose and justify their choice of an appropriate anchor and to define minimal importance on that anchor. The MIC is not an invariable characteristic of a measurement instrument, but may depend, among other things, on the perspective from which minimal importance is considered and the baseline values on the measurement instrument under study. A balance needs to be struck between the practicality of a single MIC value and the validity of a range of MIC values.     

Reading radiographs in chronological order, in pairs or as single films has important implications for the discriminative power of rheumatoid arthritis clinical trials

OBJECTIVE: To determine the influence of reading series of films in chronological order, in pairs with unknown time sequence, or as single films, on precision and sensitivity to change. METHODS: Two studies were performed with 10 and 12 patients fulfilling the American College of Rheumatology criteria. In Study 1, two sets of films with a 1 yr interval were scored in chronological order, in pairs, and as single films. In Study 2, four sets of films, with a 1 yr interval each, were scored in chronological order, as single films and as single-pair (right and left together). All films were scored with the Sharp/van der Heijde method by two independent observers. Data were analysed with a repeated measures ANOVA using a full mixed effects model. Two generalizability (G) coefficients were constructed for reliability and for change. RESULTS: Study 1: the interobserver reliability was similar for the three methods (G(reliability) chronological 0.94, paired 0.88, single 0.93); progression was a mean increase (averaged over patients, observers and methods) from 26 to 37 (P=0.046). The sensitivity for change was greater for the chronological than for the paired and single scoring (G(change) 0.39, 0.22 and 0.24, respectively). Study 2: the interobserver reliability was 0.86 for chronological, 0.76 for single-pair and 0.91 for single readings. Significantly more progression was measured with the chronological compared with the single-paired and single methods (15.9 vs 8.5 and 8.3; P=0.0001). A constant progression was suggested by chronological reading, in contrast to a stabilization in the other two methods after 1 yr. CONCLUSION: Reading films in chronological order is most sensitive to change in a time period up to 3 yr follow-up; this was already present after 1 yr, but even more pronounced with longer follow-up.     

Cystathionine-synthase-deficient patients do not use the transamination pathway of methionine to reduce hypermethioninemia and homocystinemia

Methionine is supposed to be degraded via two known routes, the transsulfuration and the transamination pathways. In particular, patients with hypermethioninemia, due to a defect in the transsulfuration pathway, may catabolize significant amounts of methionine via the transamination pathway. In this study the relative amount of methionine degraded via the transamination pathway in 17 patients with homozygous homocystinuria, due to cystathionine synthase deficiency, was compared with 23 normal subjects, and with a patient with hypermethioninemia due to a deficiency in methionine adenosyltransferase. The homocystinuric patients and the normal subjects were studied in the fasting state as well as after methionine loading (0.1 g/kg body weight). It is concluded that in cystathionine synthase deficient patients, the transamination pathway is not quantitatively important in methionine degradation despite elevated methionine levels. This is in contrast to the patient with methionine adenosyltransferase deficiency, who catabolizes at least 20% of his dietary methionine via the transamination pathway.     

Reversible nephrotoxicity of cyclosporine in rheumatoid arthritis

Irreversible nephrotoxicity has limited the use of cyclosporine in rheumatoid arthritis (RA). In a randomized clinical trial we compared 26 weeks of cyclosporine (5 mg/kg) and D-penicillamine (250 mg) treatment in 92 patients with RA with a serum creatinine less than 100 mumol/l. We adjusted the starting dose according to clinical response and side effects. During cyclosporine treatment the serum creatinine increased by median 15% (p less than 0.0001 vs baseline), quickly reversible after stopping (median followup: 1.6 years). Six patients stopped cyclosporine prematurely because of nephrotoxicity. In the D-penicillamine group the values remained at baseline.     

The effects of alpha M-foetoprotein, an acute phase protein, and BaSO4-induced injury on IgE-mediated, systemic anaphylaxis in the rat

A recently developed method for inducing fatal, IgE-mediated, bronchial and cardiovascular anaphylaxis in the rat was used to compare the effects of exogenously administered, purified alpha M-foetoprotein (alpha M FP) and BaSO4 pretreatment (as mean to induce an acute phase reaction with increased alpha M FP serum levels) with regard to mortality, bronchoconstriction and cardiovascular events. The BaSO4 pretreatment protected the rats almost completely against mortality, whereas exogenously administered alpha M FP offered no protection at all. With respect to the antigen-induced bronchoconstriction alpha M FP greatly inhibited the increase of the pulmonary resistance (RI), whereas the BaSO4 pretreatment suppressed either the dynamic lung compliance (Cdyn) or RI considerably. The cardiovascular events were only influenced by the BaSO4 pretreatment demonstrating a small but highly significant reduction of the initial fall in blood pressure together with a remarkable recovery within almost I h in the majority (91%) of the animals. Both exogenously administered alpha M FP and BaSO4 pretreatment increased the alpha M FP serum levels from a normal value of 59 +/- 4 micrograms/ml (n = 22), to 2732 +/- 252 micrograms/ml (n = 9) and 855 +/- 200 micrograms/ml (n = 22), respectively. From these data we conclude that the antianaphylactic activity of alpha M FP is limited to bronchoprotection of the more central parts of the lungs, whereas BaSO4 pretreatment covers a much broader antianaphylactic profile. This implies that BaSO4 pretreatment does not only induce alpha M FP but also other endogenous antianaphylactic factors.     

Reliability and sensitivity to change of a simplification of the Sharp/van der Heijde radiological assessment in rheumatoid arthritis.

OBJECTIVE: To determine the reliability and sensitivity to change of a simplified radiological scoring method [simple erosion narrowing score (SENS)] for rheumatoid arthritis (RA). SENS was compared to the Sharp/van der Heijde score (SHS) as a gold standard. METHODS: Sets of seven radiographs of hands and feet were taken of 20 RA patients with a wide spectrum of radiological damage. For 14 patients, these seven radiographs were taken during a follow-up period of 5 yr, and for six patients during a follow-up of 10 yr. Each set of radiographs was scored twice by the same observer (DvdH). Erosions and joint space narrowing were scored with SHS (range 0-448) in 32 and 30 joints in the hands, respectively, and both in 12 joints in the feet. SENS gives a score of 1 if there is any erosion in a joint and also 1 if there is any narrowing in the joint (range 0-86). In each case, SENS was derived from SHS. To analyse data, generalizability theory and repeated measurements ANOVA were used. RESULTS: The overall reliability coefficient was 0.81 for SHS and 0.80 for SENS. Intra-observer reliability [intraclass correlation coefficient (ICC)] was 0.99 and 0.98 for SHS and SENS, respectively. The ICC for the sensitivity to change was 0.84 for SHS and 0.88 for SENS. The smallest detectable difference (SDD) could be determined for both methods. The presence of progression based on this SDD was very comparable between the two methods. CONCLUSION: The measurement properties of SENS are good and comparable to SHS. This makes SENS suitable for use in clinical practice and in large (epidemiological) studies, especially in the first years of disease.     

Methods to monitor response to chemotherapy in non-small cell lung cancer with 18F-FDG PET.

PET using 18F-FDG is a promising technique to monitor response in oncology. Unfortunately, a multitude of analytic methods is in use. To date, it is not clear whether simplified methods could replace complex quantitative methods in routine clinical practice. The aim of this study was to select those methods that would qualify for further assessment in a future prospective response-monitoring study by comparing results with patient outcome. METHODS: Dynamic 18F-FDG PET scans were obtained on 2 groups of patients. First, 10 patients with advanced non-small cell lung cancer (NSCLC) were scanned on consecutive days before treatment to assess test-retest variability. Second, 30 scans were obtained on 19 patients with locally advanced NSCLC as part of an ongoing response-monitoring study. These scans were analyzed by 2 observers to assess observer variability. In addition, these studies were used to compare various methods with the gold standard, full kinetic analysis (nonlinear regression [NLR]). RESULTS: Using an image-derived input function, NLR showed excellent test-retest and observer agreement confirming that it could be used as a gold standard method. From a total of 34 analytic methods, 10 showed good correlation with NLR. Taking into account the degree of complexity of the methods, 4 remain for further evaluation. CONCLUSION: The optimal method for analysis of 18F-FDG PET data was determined for several levels of complexity. Four methods need to be evaluated further to determine the optimal trade-off between simplicity and accuracy for routine clinical practice.     

Recommendations for an update of 2003 European regulatory requirements for registration of drugs to be used in the treatment of RA

Since 2003, the European Medicines Agency (EMA) document, 'Points to consider on clinical investigation of medicinal products other than NSAIDs (nonsteroidal anti-inflammatory drugs) for the treatment of rheumatoid arthritis' has provided guidance for the clinical development of both biologic and non-biologic disease-modifying antirheumatic drugs (DMARDs). In the last few years, several new products have been developed or are in development for the treatment of RA, which offer significant efficacy with regard to disease control, including prevention of structural damage and disability. Concurrently, novel insights have been gained with respect to the assessment of disease activity, joint damage and disability. New treatment strategies have been established which relate to early therapy, tight control and rapid switching of medication. Accordingly, several new EULAR/ACR recommendations have been or are being developed. Several important additions and changes are needed in the 2003 guidance to incorporate the current scientific knowledge into clinical trial design for the development of future products. Under the auspices of the Group for the Respect of Ethics and Excellence in Science (GREES), a group of experts in the field of RA and clinical trial design met to provide a consensus recommendation for an update to the 2003 EMA guidance document.     

Minimal clinically important improvement and patient acceptable symptom state for subjective outcome measures in rheumatic disorders

The concepts of minimal clinically important improvement (MCII) and patient acceptable symptomatic state (PASS) could help in interpreting results of trials involving patient-reported outcomes by translating the response at the group level (change in mean scores) into more clinically meaningful information by addressing the patient level as "therapeutic success (yes/no)." The aims of the special interest group (SIG) at OMERACT 8 were to discuss specific issues concerning the MCII and PASS concepts, especially the wording of the external anchor questions used to determine the MCII and PASS estimates, and to move toward a consensus for the cutoff values to use as the MCII and PASS in the different outcome criteria. The purpose of this SIG at OMERACT 8 was to inform participants of the MCII and PASS concepts and to agree on MCII and PASS values for pain, patient global assessment, and functional impairment.     

The World Health Organisation International Classification of Functioning, Disability and Health: a conceptual model and interface for the OMERACT process

"What to measure" refers to domains stable over time. "How to measure" is constantly evolving. Lacking a common terminology and common underlying conceptual model of functioning and disability, what and how to measure have been described differently in the various OMERACT Core Sets. With the approval of the International Classification of Functioning, Disability and Health (ICF) by the World Health Assembly in 2001, we now have a universally conceptual model that integrates the biomedical and societal model of functioning and disability. The so-called ICF Core Sets can be used as a basis for the further specification of OMERACT domains addressing aspects of functioning. In line with the successful approach taken by OMERACT, it is suggested to comprehensively specify the domain "function" when defining "what should be measured," and only then to recommend how to measure or which health status measure to use. We recommend comparing the specifications of domains addressing aspects of functioning of OMERACT Core Sets already established with the ICF Core Sets, and examine whether the ICF Core Sets may be useful for the further specification of these domains.