Multiple sclerosis (MS) is a chronic, autoimmune and neurodegenerative disorder of the central nervous system (CNS) characterized by inflammation, demyelination and neuronal loss. MS represents the leading cause of non-traumatic neurologic disability in young and middle-aged adults, affecting an estimated 2.5 million individuals worldwide . About 85% of patients begin with the Relapse Remitting form of MS (RRMS) which is characterised by episodes of symptoms followed by resolution, at least partly, within days to months [2, 3]. The long term clinical effects of MS often lead to serious disability. Symptoms of MS are wide ranging and can include weakness of the limbs (particularly the legs), fatigue, unsteadiness, difficulty with bladder control, visual changes due to the involvement of the optic nerve, vertigo, facial numbness or weakness or double vision . In addition, depression occurs in about a quarter of patients . Unsurprisingly, the disease can have major detrimental effects on a patient's QoL [3, 6, 7].
Measuring the wide ranging effects of MS is important for developing understanding and treatment of this disease. The Patient Reported Indices for Multiple Sclerosis (PRIMUS) was developed to capture the overall impact of MS from the patient's perspective . This instrument consists of three distinct scales specific to MS; symptoms, activity limitations and quality of life (QoL), each designed to be used in combination or as a standalone measure. Scale content was generated directly from MS patients and, consequently closely represents patients' experience of MS. As fatigue is present in about three quarters of patients  the Unidimensional Fatigue Impact scale (U-FIS)  was developed in parallel with the PRIMUS scales to provide an index of the impact of fatigue associated with MS. The PRIMUS and U-FIS scales were developed and validated in patients representing the most common MS sub-types; RRMS, Secondary Progressive MS and Primary Progressive MS [8, 10]. Data from a large 12 month efficacy trial were made available to evaluate the validity of the instruments further specifically for RRMS. These data also provided an opportunity to investigate how to interpret scores for the PRIMUS and U-FIS.
One of the most commonly used approaches for investigating how to interpret scores on Patient Reported Outcome (PRO) scales has been through the calculation of a minimum score that can be considered to be clinically meaningful. This score can then be used to help interpret treatment response during therapeutic trials. Calculation of this score has been referred to as the Minimal Important Difference (MID) , meaningful change  and minimal clinically significant difference . More recently the term Responder Definition (RD) has replaced previous terminology .
No single method for estimating the RD is widely accepted. Approaches can be classified broadly into anchor-based and distribution-based approaches. Anchor-based approaches involve relating change scores on the PRO to change in a factor of known importance. These methods usually involve using other PROs, [11, 15, 16] clinical variables [17, 18] or patient global rating of change questions [12, 19, 20] as an anchor. Each approach has strengths and limitations. Other comparator instruments can only be used when the instruments are suitably related to the testing instrument and cover issues important and relevant to the patient . Some authors have suggested that a correlation of 0.5 is necessary between the anchor and main instrument in order to ensure adequate relatedness [15, 16]. In these cases it is also useful if previous research has investigated the RD of the comparator instrument. Clinical variables can provide useful markers for interpreting scores on PROs but they do not provide minimal important difference estimates per se. These are most useful when other information for estimating RD is unavailable. Global Rating of Change (GRC) questions generally have multiple Likert type response options ranging from 'very much worse' to 'very much better'. Change scores for those individuals responding 'a little' or 'moderately' improved are used to estimate the RD. Although global rating of change questions are easy to administer the reliability of such methods is questionable. Doubt exists about whether patients can recall their health over periods of time and it is unknown whether patients respond primarily in relation to their current health rather than their change in health . It has also been argued that estimation of RD should not be based on GRC items alone .
Distribution-based approaches assess the distribution of scores on the PRO and attempt to identify a score that may be considered important above the 'statistical noise' of the measure. Various distribution-based approaches have been suggested including effect size , half a standard deviation , the standard error of measurement (SEM)  and the standard response mean (SRM) . These different approaches usually produce different magnitudes of RD. Furthermore, distribution-based estimates can sometimes differ considerably from those obtained using anchor-based methods .
No previous study has attempted to determine the RD of the PRIMUS and U-FIS. The aim of the present study was twofold. First, to provide further evidence of the validity of the PRIMUS and U-FIS in a RRMS sample. Secondly, to investigate the RD of the PRIMUS and U-FIS scales.