Journal of the Peripheral Nervous System 20:333–340 (2015)
RESEARCH REPORT
Improving assessment in small fiber neuropathy Brigitte A. Brouwer1 , Mayienne Bakkers2 , Janneke G. J. Hoeijmakers2 , Catharina G. Faber2 , and Ingemar S. J. Merkies2,3 1 Department of Anesthesiology and Pain Management; 2 Department of Neurology, Maastricht University Medical Center, PO Box 5800, 6202 AZ, Maastricht; and 3 Department of Neurology, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, The Netherlands
Abstract Interval measures at the impairment level addressing symptoms and at the activity/participation level addressing daily and social restrictions have not been developed for small fiber neuropathy (SFN). We developed an SFN-specific Rasch-built overall disability scale (SFN-RODS©), an activity/participation scale at the interval level. A preliminary SFN-RODS containing 146 activity/participation items was assessed twice (reliability studies) in 238 patients with SFN. The ordinal-based 13-item SFN-symptoms inventory questionnaire (SFN-SIQ©) and pain-visual-analogue-scale were also assessed (validity studies). The pre-SFN-RODS and SFN-SIQ data were subjected to the Rasch analyses. The pre-SFN-RODS did not meet Rasch model expectations. Based on requirements, such as misfit statistics, differential item functioning, and local dependency, items were systematically removed and model fit improved. Finally, a 32-item SFN-RODS© scale was constructed that fulfilled all Rasch requirements, demonstrating acceptable reliability and validity scores. The 13-item SFN-SIQ© was successfully transformed to an interval Rasch-built measure fulfilling model’s requirements. In conclusion, the 32-item SFN-RODS© is a disease-specific interval measure suitable for detecting activity limitations and participation restrictions in patients with SFN. The 13-item SFN-SIQ© was transformed through Rasch to an interval measure. The use of these scales is recommended in future clinical interventional trials involving patients with SFN. Key words: outcome research, peripheral neuropathy, Rasch-built overall disability scale, small fiber neuropathy
Introduction
minimum overall incidence and prevalence of SFN are estimated to be 12/100.000 and 53/100.000, respectively (Peters et al., 2013). However, these numbers are expected to rise with the increased awareness of SFN worldwide. With the recognition of SFN, future focus should be on interventional trials aiming to alleviate SFN-related symptoms such as neuropathic pain and autonomic complaints, improving quality of life in patients with SFN. Causative treatment of underlying conditions (e.g., diabetes mellitus) should also be part of these efforts (Hoeijmakers et al., 2012). However, the effect of medical intervention on the course of pure SFN has not been examined thus far. At the current
Small fiber neuropathy (SFN) has been gaining international recognition in the last 2 decades since the availability of skin biopsy that contributes to its diagnosis (Wang et al., 1990; Lauria et al., 2010b; 2012; Hoeijmakers et al., 2012). SFN is considered a debilitating disorder that may have a severe negative effect on quality of life expectations (Bakkers et al., 2014). The
Address correspondence to: Ingemar S. J. Merkies, MD, PhD, Department of Neurology, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, The Netherlands. Tel: +(31)-23-8907335; Fax: +(31)-23-8907341; E-mail: [email protected]. © 2015 Peripheral Nerve Society
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stage, efforts are being made to develop effective pharmacotherapies such as selective sodium channel blockers, which may prove effective, especially in patients with SFN-related SCN9A, SCN10A and SCN11A mutations (Lai et al., 2003; Amir et al., 2006; Faber et al., 2012a; 2012b; Hoeijmakers et al., 2012; Huang et al, 2014). Proper measurement of efficacy of future therapeutic agents in SFN should be performed using outcome measures that have a high level of assessment precision, that is, being at the interval or ratio level rather than using ordinal-based measures (Merbitz et al., 1989; Wright and Linacre, 1989). Apart from pain outcome measures such as the Visual Analogue Scale (VAS), additional proper outcome measures are needed at the impairment and activity and participation levels according to the WHO international classification of Functioning, Disability, and Health (Maxwell, 1978; World Health Organization, 2001). These scales should also fulfill modern clinimetric requirements (Merkies et al., 2012). At the current stage, no activity and participation scale has been developed specifically for SFN. Also, the previously used SFN-symptoms inventory questionnaire (SFN-SIQ) is ordinal-based and should therefore be transformed to an interval measure prior to its use in interventional trials (Wright and Linacre, 1989; Bakkers et al., 2009). The primary aim of this paper is to develop a Rasch-built overall disability scale specifically designed for patients with SFN (SFN-RODS©) and to examine its scientific soundness (Streiner and Norman, 1998). In addition, a transformation through Rasch analyses of the ordinal-based SFN-SIQ© into an interval measures will also be addressed.
study were age 18 years and older and informed consent before study enrollment. The local medical ethics committee approved the protocol. SFN-associated conditions were documented.
Questionnaire development As previously reported, published standardized requirements for scale development were applied to create the SFN disease-specific activity and participation scale (Streiner and Norman, 1998; van Nes et al., 2011). Patients diagnosed with SFN were requested to complete a list of previously selected and reported pre-phase 146 activity and participation items (van Nes et al., 2011), scoring each item as (0) unable to perform, (1) able to perform, but with difficulty, or (2) easily performed, without difficulty. An item was scored (3) if it was not applicable to the patient.
Additional outcome measure The Pain-VAS (100 mm) was assessed to capture the magnitude of pain in the examined patients (Maxwell, 1978). In addition, the previously used SFN-SIQ was also completed by the patients (Faber et al., 2012a). The SFN-SIQ is an ordinal-based multi-item composite measure addressing 13 SFN-related symptoms: changes in sweating pattern, sudden diarrhea, constipation, urination problems (incontinence and hesitation), dry eyes, dry mouth, dizziness when standing up from sitting/supine, palpitations, hot flashes, sensitive skin of the legs, burning feet, sheet intolerance, and restless legs; each item being scored as (0) never, (1) sometimes, (2) often, (3) always present.
Assessment procedure Standardized instructions were given to patients before completion of the selected outcome measures. The pre-phase SFN-RODS questionnaire was completed twice (test-retest reliability study; interval ∼4 weeks; first assessment: n = 238 patients, second assessment; n = 168 returned the questionnaire). In case of any doubt completing an item/task, the patient was requested to choose the answer as close as possible to his/her ability to complete such a task. Patients were also instructed to tick “not applicable” only in exceptional cases when the patient has a real problem determining any of the other options related to the item of interest. The Pain-VAS and SFN-SIQ were assessed once in all patients (validity studies).
Methods Patients, eligibility, and ethical approval A total of 238 patients were systematically entered into a database and were recruited between November 2009 and February 2013 at our SFN Center at the Maastricht University Medical Center. All participants fulfilled the international criteria for SFN (Tesfaye et al., 2010; Lauria et al., 2012). In brief, patients should have at least two complaints related to small nerve fiber dysfunction (pain [burning, sunburn-like, paroxysmal, pruritic, deep], burning feet, and autonomic dysfunction), and reduced intra-epidermal nerve fiber density (IENFD) when compared to age- and sex-matched normative values and/or abnormal temperature threshold testing (TTT), without signs of large fiber dysfunction or central nervous disorders at neurological examination and nerve conduction studies (Yarnitsky and Sprecher, 1994; Lauria et al., 2010a). Further eligibility for the
Rasch analyses and statistical aspects Rasch description The pre-phase SFN-RODS was subjected to the Rasch Unidimensional Measurement Model 334
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Figure 1. Selection of patients with SFN for this study. IENFD, intra-epidermal nerve fiber density; RODS©, Rasch-built overall disability scale; SFN-SIQ©, small fiber neuropathy n = 13 symptoms inventory questionnaire; TTT, temperature threshold testing.
(PSI). A PSI should be ≥0.7 for proper comparison of groups (Fisher, 1992). Test-retest reliability studies (items’ weights [locations] and patients’ ability locations [both in logits]) were also performed to determine the consistency of the final scale created (Wright and Stone, 1979). Reliability was quantified by calculating the intra-class correlation coefficient through regression studies (expressed as R2 ). External validity of the final SFN-RODS© scale was determined through correlation studies with the Pain-VAS and the Rasch-transformed (RT) interval SFN-SIQ©, separately (one-way ANOVA modeling with corrections for multiple comparisons) (Bland and Altman, 1995). The 13-item SFN-SIQ© was also subjected to Rasch analysis (RT-SFN-SIQ), and PSI and fit statistical values were determined. Further analyses were undertaken using Stata 12.0 for Windows XP.
(RUMM2030) to determine whether model expectations would be met (Andrich et al., 2010). Educational papers on this methodology have been described thoroughly elsewhere (Rasch, 1960; Pallant and Tennant, 2007; Tennant and Conaghan, 2007; van Nes et al., 2011). In brief, Rasch technique transforms ordinal obtained scores into interval measures that have a higher level of measurement precision. Analyses were performed to obtain a final constructed SFN-RODS scale that would fulfill all Rasch model expectations, such as proper fit statistical parameters, lack of differential item functioning (DIF), no disordered thresholds or local dependency, and fulfillment of unidimensionality (Fisher, 1992; Tennant and Conaghan, 2007). For the purposes of this study, the following person factors were examined as potential confounding factors as part of the scale’s construction: age (15% of the items were not completed, leaving 238 patients’ records for further analyses (Fig. 1). These patients completed the 146-item pre-SFN-RODS and the additional scales (Pain-VAS and SFN-SIQ). Patients’ demographics are presented in Table 1. There were slightly more women in the cohort and approximately half of the patients had an idiopathic SFN (51.3%). The SFN-related symptoms in these patients are presented in Table 2, with burning feet being most frequently reported. The findings in the idiopathic group did not differ from the whole group. For Rasch analyses, all items scored 3 (“not applicable”) on the pre-phase SFN-RODS were re-coded as missing data. Subsequently, through data quality control, 18 items with >15% missing values were omitted. The remaining 128 items were subjected to Rasch analyses.
Step 3 A total of n = 16 items demonstrated misfit statistics and/or fit residuals exceeding ±2.5 and were removed stepwise (n = 85 items remaining). Step 4 A large amount of local dependency findings were found between items. All item sets with correlations above 0.30 were evaluated starting with the highest correlations (>0.7, subsequently >0.6, etc., to >0.30). Of each item set, the item showing less clinical relevance (face and content validity based on opinion of two experts having consensus) and with most overor under-discrimination on its category probability curve was removed. Eventually, a total of 53 items were removed stepwise. After completing these steps, we succeeded in constructing the 32-item final SFN-RODS© that met all Rasch model expectations (item fit residuals: mean: −0.266, SD: 1.032; person fit residuals: mean: −0.368, SD: 0.979; item-trait chi-square: p-value = 0.69, DF = 96) (Fig. 2). Based on the first principal component analysis, two subsets of items were formed (six most positively loading vs. six most negatively loading items) and the independent t-tests between these two subsets suggested
Initial Rasch analyses on the pre-phase SFN-RODS The pre-phase 128-item SFN-RODS scale did not meet Rasch model expectations. Both person’s and item’s fit residuals showed acceptable fit statistics (item’s statistics: mean: −0.309, SD: 1.325; person’s statistics: −0.374, SD: 1.325). The significant chi-square probability (p < 0.00001) demonstrated no invariance of items–trait interactions and a proportion of 0.13 336
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Table 2. SFN-related symptoms found in the cohort of patients examined. Symptoms reported in SFN patients* Whole cohort (n = 238)/only idiopathic SFN patients (n = 122) Presence of symptoms
Changed sweating pattern Diarrhea Constipation Micturition problems Dry eyes Dry mouth Dizziness on standing Palpitations Hot flashes Sensitive skin Burning feet Sheet intolerance legs Restless legs
Never
Sometimes
Often
Always
24.2/21.2 47.0/48.7 46.6/50.4 37.0/36.1 40.9/41.5 25.9/28.2 33.2/33.6 38.4/45.4 37.0/39.0 24.3/24.8 8.5/9.4 27.1/28.8 16.6/15.1
42.0/46.6 36.0/35.0 33.1/31.1 34.9/32.8 29.1/26.3 36.4/33.3 49.4/52.1 48.5/42.9 34.9/38.1 23.8/22.2 17.4/14.5 30.1/31.4 31.1/30.3
26.7/28.0 14.8/14.5 15.7/11.8 20.2/21.0 19.0/22.0 29.7/29.1 14.0/13.5 11.8/10.9 26.0/21.2 23.8/27.4 35.6/38.5 25.0/21.2 31.5/33.6
7.2/4.2 2.2/1.7 4.7/6.7 8.0/10.1 11.0/10.2 8.1/9.4 3.4/0.8 1.3/0.8 2.1/1.7 28.1/25.6 38.6/37.6 17.8/18.6 20.9/21.0
Burning feet is most frequently reported. SFN, small fiber neuropathy. *Data expressed as percentages of responders.
acceptable unidimensionality (0.055; 95% CI: 0.027–0.082). The item “brush your teeth” was the easiest item to perform, while “walk at least three flights of stairs” was the most difficult to accomplish (Fig. 2). The item difficulty ranged from −2.15 to 3.012 logits. Patient’s location ranged from −2.377 to 6.629 with 11.3% (27 of 238) having a maximum score.
the Pain-VAS and RT-SFN-SIQ© (Fig. 3). A significant trend was seen showing decreasing activity and participation ability of patients (lower SFN-RODS values) with increasing pain intensity and severity of SFN-related complaints (SFN-SIQ scores). The SFN-SIQ findings explained 26% of the SFN-RODS findings (p < 0.0001). Internal reliability for the final SFN-RODS© remained robust as indicated by a PSI of 0.91. Also, acceptable test-retest reliability scores were obtained for items’ weights and patients’ abilities (Fig. 4). The final SFN-RODS© and SFN-SIQ© are presented as Tables S1 and S2.
Rasch analyses of the SFN-SIQ© The 13 items were subjected to Rasch and almost all model’s expectations were directly met: item’s statistics: mean: 0.21, SD: 0.662; person’s statistics: −0.159; SD: 1.083, chi-square probability p = 0.80; unidimensionality was also met (two subsets of three items): proportion of significant t-tests: 0.046 (95% confidence interval: 0.018–0.074). PSI was also acceptable (0.77). None of the items had misfit statistics and their corresponding fit residuals fell within the allowed ±2.5 boundaries (Fig. S1). No local dependency and disordered thresholds were seen. No item bias was seen for all items except for “hot flashes” (uniform DIF) and “skin sensitivity of the legs” (non-uniform DIF) on person factor sex. These two items were split creating specific items for females and males, respectively. The statistics hardly changed: item’s statistics: mean: 0.131, SD: 0.735; person’s statistics: −0.151; SD: 1.074, chi-square probability p = 0.47; DF: 45. PSI remained unchanged (0.77). Therefore, to assure simplicity, the RT-SFN-SIQ data were used in the further analyses.
Discussion This paper presents two modern interval outcome measures, the SFN-RODS© and SFN-SIQ©, that fulfilled Rasch model expectations as part of a movement in improving the clinical assessment and care of patients suffering from SFN (Tennant and Conaghan, 2007). The SFN-SIQ© captures SFN-specific symptoms and the SFN-RODS© is the first interval measure specifically constructed to assess activity and participation restrictions in this condition. Acceptable validity and reliability values were also seen (good PSIs, see also Figs 3 and 4). In particular, increasing pain intensity (as captured with the VAS) and higher scores on the SFN-SIQ© (reflecting greater magnitude of symptoms) were related to a decrease in daily and social functioning (lower SFN-RODS© scores). The magnitude of neuropathic pain may lead to a diminished overall well-being and quality of life expectations, as
Validity and reliability studies The final 32-item SFN-RODS© scale demonstrated acceptable discriminative validity when correlated with 337
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Figure 2. Threshold map and item difficulty location for the final SFN-RODS©. Blue sections (0) = unable to perform; red sections (1) = able to perform, but with difficulty; green sections (2) = able to perform, without difficulty. A gradual shift is seen: the blue section of the item “able to brush your teeth” (the easiest item) is much shorter than the blue section of the item “able to walk at least 3 flights of stairs” (the most difficult items). The right panel presents the overall item difficulty locations for each item with the corresponding SE. RODS, Rasch-built overall disability scale; SFN, small fiber neuropathy.
Figure 3. (A) Association between SFN-RODS© and Pain-VAS. (B) Association between SFN-RODS© and SFN-SIQ©. A high patient location on the SFN-RODS© indicates a better activity and participation ability. With the increasing intensity of complaints present (as captured with the SFN-SIQ©) and higher pain scores, more activity and participation restrictions were seen. The mean pain VAS score of the cohort was 50.5 (SD: 27.3) and ranged from 0 to 100. NS, not significant; RODS, Rasch-built overall disability scale; SFN, small fiber neuropathy; SIQ, symptoms inventory questionnaire; VAS, Visual Analogue Scale.
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Figure 4. Test-retest reliability findings for the final SFN-RODS©. (A) Item difficulty hierarchy of the final SFN-RODS© in the first vs. the second assessment (interval 1 year). Almost all items (dots) were located within the 95% confidence interval (solid lines) reflecting ideal reliability. (B) Patients’ location in the first assessment vs. the second assessment. Most person scores (dots) were located within the 95% confidence interval (solid lines). RODS, Rasch-built overall disability scale; SFN, small fiber neuropathy.
has been reported previously (Poliakov and Toth, 2011; Bakkers et al., 2014). The development of the SFN-RODS© and transforming the SFN-SIQ© into an interval measure contribute to the pallet needed to evaluate the effect of SFN at all levels of assessing outcome, ranging from pathology (skin biopsy), to impairments (biophysical properties; SFN-SIQ©, pain assessment), to activity limitations and participation restrictions (newly developed SFN-RODS©), and to quality of life expectations (as demonstrated recently using the SF-36), which reflects the WHO framework of understanding the consequences of an illness (Ware et al., 2000; World Health Organization, 2001; Bakkers et al., 2009; Faber et al., 2012a; Hoeijmakers et al., 2012; Lauria et al., 2012). In addition, the Rasch-built SFN-RODS© and SFN-SIQ© outcomes also reflect a higher level of measurement precision, bypassing the known deficiencies of ordinal-based scales (Merbitz et al., 1989; Wright and Linacre, 1989; DeVellis, 2006). Some methodological issues related to this study should be addressed. First, the interval between the first and second assessment of the pre-phase SFN-RODS© was 1 year. It is conceivable that some patients may have experienced deterioration or even improvement, which may have influenced the reliability scores. However, most patients were located within the 95% confidence intervals, indicating a clinical unchanged status at the activity and participation level of assessing outcome (Fig. 3). Second, we have used the initial data for the SFN-SIQ© after subjecting these to Rasch analyses, as the scale demonstrated outstanding overall fit statistics from the first analysis. Only two items showed DIF. After splitting these two items, the statistics only change at the decimal levels. It is believed that these minor changes would not be of any influence on the correlations when compared to the data entry findings. Third, at the current stage, the responsiveness of the SFN-RODS©
and SFN-SIQ© has not been determined yet (Liang, 1995). Future interventional trials in SFN are needed to examine this. At the current stage, the assessment of pain should still be considered as the primary outcome in SFN, as has been suggested by the IMMPACT for all painful neuropathic studies (Dworkin et al., 2009). Fourth, SFN-related complaints not only have a large effect on quality of life expectations as recently reported by our group (Bakkers et al, 2014), but also on daily/social activities as shown in this study. However, these findings need validation in other SFN cohorts, as our patients were all Dutch. In conclusion, two disease-specific scales for SFN are presented: the RT-SFN-SIQ© assessing outcome at the impairment level and the SFN-RODS© that captures activity limitations and participation restrictions. Both scales have demonstrated good modern scientific soundness. Their use is therefore suggested in future clinical SFN trials to capture possible efficacy of an intervention.
Acknowledgements B. A. B., M. B., and J. G. J. H. were involved in recruitment, data collection, and preparation of the final report. C. G. F. and I. S. J. M. were involved in study design, statistical analysis, and preparation of the final report. B. A. B., M. B., and J. G. J. H. report no disclosures. C. G. F. reports grants from the European Union 7th Framework Program (grant number 602273), and the Prinses Beatrix Spierfonds (W.OR12-01). I. S. J. M. served on a scientific advisory board for CSL Behring, has received funding for travel from Talecris Biotherapeutics, and has received research support from the European Union 7th Framework Program (grant number 602273), the GBS/CIDP International Foundation, the Talents Program foundation, and the Peripheral Nerve Society. 339
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Supporting Information Additional Supporting Information may be found in the online version of this article.
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RESEARCH REPORT
Improving assessment in small fiber neuropathy Brigitte A. Brouwer1 , Mayienne Bakkers2 , Janneke G. J. Hoeijmakers2 , Catharina G. Faber2 , and Ingemar S. J. Merkies2,3 1 Department of Anesthesiology and Pain Management; 2 Department of Neurology, Maastricht University Medical Center, PO Box 5800, 6202 AZ, Maastricht; and 3 Department of Neurology, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, The Netherlands
Abstract Interval measures at the impairment level addressing symptoms and at the activity/participation level addressing daily and social restrictions have not been developed for small fiber neuropathy (SFN). We developed an SFN-specific Rasch-built overall disability scale (SFN-RODS©), an activity/participation scale at the interval level. A preliminary SFN-RODS containing 146 activity/participation items was assessed twice (reliability studies) in 238 patients with SFN. The ordinal-based 13-item SFN-symptoms inventory questionnaire (SFN-SIQ©) and pain-visual-analogue-scale were also assessed (validity studies). The pre-SFN-RODS and SFN-SIQ data were subjected to the Rasch analyses. The pre-SFN-RODS did not meet Rasch model expectations. Based on requirements, such as misfit statistics, differential item functioning, and local dependency, items were systematically removed and model fit improved. Finally, a 32-item SFN-RODS© scale was constructed that fulfilled all Rasch requirements, demonstrating acceptable reliability and validity scores. The 13-item SFN-SIQ© was successfully transformed to an interval Rasch-built measure fulfilling model’s requirements. In conclusion, the 32-item SFN-RODS© is a disease-specific interval measure suitable for detecting activity limitations and participation restrictions in patients with SFN. The 13-item SFN-SIQ© was transformed through Rasch to an interval measure. The use of these scales is recommended in future clinical interventional trials involving patients with SFN. Key words: outcome research, peripheral neuropathy, Rasch-built overall disability scale, small fiber neuropathy
Introduction
minimum overall incidence and prevalence of SFN are estimated to be 12/100.000 and 53/100.000, respectively (Peters et al., 2013). However, these numbers are expected to rise with the increased awareness of SFN worldwide. With the recognition of SFN, future focus should be on interventional trials aiming to alleviate SFN-related symptoms such as neuropathic pain and autonomic complaints, improving quality of life in patients with SFN. Causative treatment of underlying conditions (e.g., diabetes mellitus) should also be part of these efforts (Hoeijmakers et al., 2012). However, the effect of medical intervention on the course of pure SFN has not been examined thus far. At the current
Small fiber neuropathy (SFN) has been gaining international recognition in the last 2 decades since the availability of skin biopsy that contributes to its diagnosis (Wang et al., 1990; Lauria et al., 2010b; 2012; Hoeijmakers et al., 2012). SFN is considered a debilitating disorder that may have a severe negative effect on quality of life expectations (Bakkers et al., 2014). The
Address correspondence to: Ingemar S. J. Merkies, MD, PhD, Department of Neurology, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, The Netherlands. Tel: +(31)-23-8907335; Fax: +(31)-23-8907341; E-mail: [email protected]. © 2015 Peripheral Nerve Society
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stage, efforts are being made to develop effective pharmacotherapies such as selective sodium channel blockers, which may prove effective, especially in patients with SFN-related SCN9A, SCN10A and SCN11A mutations (Lai et al., 2003; Amir et al., 2006; Faber et al., 2012a; 2012b; Hoeijmakers et al., 2012; Huang et al, 2014). Proper measurement of efficacy of future therapeutic agents in SFN should be performed using outcome measures that have a high level of assessment precision, that is, being at the interval or ratio level rather than using ordinal-based measures (Merbitz et al., 1989; Wright and Linacre, 1989). Apart from pain outcome measures such as the Visual Analogue Scale (VAS), additional proper outcome measures are needed at the impairment and activity and participation levels according to the WHO international classification of Functioning, Disability, and Health (Maxwell, 1978; World Health Organization, 2001). These scales should also fulfill modern clinimetric requirements (Merkies et al., 2012). At the current stage, no activity and participation scale has been developed specifically for SFN. Also, the previously used SFN-symptoms inventory questionnaire (SFN-SIQ) is ordinal-based and should therefore be transformed to an interval measure prior to its use in interventional trials (Wright and Linacre, 1989; Bakkers et al., 2009). The primary aim of this paper is to develop a Rasch-built overall disability scale specifically designed for patients with SFN (SFN-RODS©) and to examine its scientific soundness (Streiner and Norman, 1998). In addition, a transformation through Rasch analyses of the ordinal-based SFN-SIQ© into an interval measures will also be addressed.
study were age 18 years and older and informed consent before study enrollment. The local medical ethics committee approved the protocol. SFN-associated conditions were documented.
Questionnaire development As previously reported, published standardized requirements for scale development were applied to create the SFN disease-specific activity and participation scale (Streiner and Norman, 1998; van Nes et al., 2011). Patients diagnosed with SFN were requested to complete a list of previously selected and reported pre-phase 146 activity and participation items (van Nes et al., 2011), scoring each item as (0) unable to perform, (1) able to perform, but with difficulty, or (2) easily performed, without difficulty. An item was scored (3) if it was not applicable to the patient.
Additional outcome measure The Pain-VAS (100 mm) was assessed to capture the magnitude of pain in the examined patients (Maxwell, 1978). In addition, the previously used SFN-SIQ was also completed by the patients (Faber et al., 2012a). The SFN-SIQ is an ordinal-based multi-item composite measure addressing 13 SFN-related symptoms: changes in sweating pattern, sudden diarrhea, constipation, urination problems (incontinence and hesitation), dry eyes, dry mouth, dizziness when standing up from sitting/supine, palpitations, hot flashes, sensitive skin of the legs, burning feet, sheet intolerance, and restless legs; each item being scored as (0) never, (1) sometimes, (2) often, (3) always present.
Assessment procedure Standardized instructions were given to patients before completion of the selected outcome measures. The pre-phase SFN-RODS questionnaire was completed twice (test-retest reliability study; interval ∼4 weeks; first assessment: n = 238 patients, second assessment; n = 168 returned the questionnaire). In case of any doubt completing an item/task, the patient was requested to choose the answer as close as possible to his/her ability to complete such a task. Patients were also instructed to tick “not applicable” only in exceptional cases when the patient has a real problem determining any of the other options related to the item of interest. The Pain-VAS and SFN-SIQ were assessed once in all patients (validity studies).
Methods Patients, eligibility, and ethical approval A total of 238 patients were systematically entered into a database and were recruited between November 2009 and February 2013 at our SFN Center at the Maastricht University Medical Center. All participants fulfilled the international criteria for SFN (Tesfaye et al., 2010; Lauria et al., 2012). In brief, patients should have at least two complaints related to small nerve fiber dysfunction (pain [burning, sunburn-like, paroxysmal, pruritic, deep], burning feet, and autonomic dysfunction), and reduced intra-epidermal nerve fiber density (IENFD) when compared to age- and sex-matched normative values and/or abnormal temperature threshold testing (TTT), without signs of large fiber dysfunction or central nervous disorders at neurological examination and nerve conduction studies (Yarnitsky and Sprecher, 1994; Lauria et al., 2010a). Further eligibility for the
Rasch analyses and statistical aspects Rasch description The pre-phase SFN-RODS was subjected to the Rasch Unidimensional Measurement Model 334
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Figure 1. Selection of patients with SFN for this study. IENFD, intra-epidermal nerve fiber density; RODS©, Rasch-built overall disability scale; SFN-SIQ©, small fiber neuropathy n = 13 symptoms inventory questionnaire; TTT, temperature threshold testing.
(PSI). A PSI should be ≥0.7 for proper comparison of groups (Fisher, 1992). Test-retest reliability studies (items’ weights [locations] and patients’ ability locations [both in logits]) were also performed to determine the consistency of the final scale created (Wright and Stone, 1979). Reliability was quantified by calculating the intra-class correlation coefficient through regression studies (expressed as R2 ). External validity of the final SFN-RODS© scale was determined through correlation studies with the Pain-VAS and the Rasch-transformed (RT) interval SFN-SIQ©, separately (one-way ANOVA modeling with corrections for multiple comparisons) (Bland and Altman, 1995). The 13-item SFN-SIQ© was also subjected to Rasch analysis (RT-SFN-SIQ), and PSI and fit statistical values were determined. Further analyses were undertaken using Stata 12.0 for Windows XP.
(RUMM2030) to determine whether model expectations would be met (Andrich et al., 2010). Educational papers on this methodology have been described thoroughly elsewhere (Rasch, 1960; Pallant and Tennant, 2007; Tennant and Conaghan, 2007; van Nes et al., 2011). In brief, Rasch technique transforms ordinal obtained scores into interval measures that have a higher level of measurement precision. Analyses were performed to obtain a final constructed SFN-RODS scale that would fulfill all Rasch model expectations, such as proper fit statistical parameters, lack of differential item functioning (DIF), no disordered thresholds or local dependency, and fulfillment of unidimensionality (Fisher, 1992; Tennant and Conaghan, 2007). For the purposes of this study, the following person factors were examined as potential confounding factors as part of the scale’s construction: age (15% of the items were not completed, leaving 238 patients’ records for further analyses (Fig. 1). These patients completed the 146-item pre-SFN-RODS and the additional scales (Pain-VAS and SFN-SIQ). Patients’ demographics are presented in Table 1. There were slightly more women in the cohort and approximately half of the patients had an idiopathic SFN (51.3%). The SFN-related symptoms in these patients are presented in Table 2, with burning feet being most frequently reported. The findings in the idiopathic group did not differ from the whole group. For Rasch analyses, all items scored 3 (“not applicable”) on the pre-phase SFN-RODS were re-coded as missing data. Subsequently, through data quality control, 18 items with >15% missing values were omitted. The remaining 128 items were subjected to Rasch analyses.
Step 3 A total of n = 16 items demonstrated misfit statistics and/or fit residuals exceeding ±2.5 and were removed stepwise (n = 85 items remaining). Step 4 A large amount of local dependency findings were found between items. All item sets with correlations above 0.30 were evaluated starting with the highest correlations (>0.7, subsequently >0.6, etc., to >0.30). Of each item set, the item showing less clinical relevance (face and content validity based on opinion of two experts having consensus) and with most overor under-discrimination on its category probability curve was removed. Eventually, a total of 53 items were removed stepwise. After completing these steps, we succeeded in constructing the 32-item final SFN-RODS© that met all Rasch model expectations (item fit residuals: mean: −0.266, SD: 1.032; person fit residuals: mean: −0.368, SD: 0.979; item-trait chi-square: p-value = 0.69, DF = 96) (Fig. 2). Based on the first principal component analysis, two subsets of items were formed (six most positively loading vs. six most negatively loading items) and the independent t-tests between these two subsets suggested
Initial Rasch analyses on the pre-phase SFN-RODS The pre-phase 128-item SFN-RODS scale did not meet Rasch model expectations. Both person’s and item’s fit residuals showed acceptable fit statistics (item’s statistics: mean: −0.309, SD: 1.325; person’s statistics: −0.374, SD: 1.325). The significant chi-square probability (p < 0.00001) demonstrated no invariance of items–trait interactions and a proportion of 0.13 336
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Table 2. SFN-related symptoms found in the cohort of patients examined. Symptoms reported in SFN patients* Whole cohort (n = 238)/only idiopathic SFN patients (n = 122) Presence of symptoms
Changed sweating pattern Diarrhea Constipation Micturition problems Dry eyes Dry mouth Dizziness on standing Palpitations Hot flashes Sensitive skin Burning feet Sheet intolerance legs Restless legs
Never
Sometimes
Often
Always
24.2/21.2 47.0/48.7 46.6/50.4 37.0/36.1 40.9/41.5 25.9/28.2 33.2/33.6 38.4/45.4 37.0/39.0 24.3/24.8 8.5/9.4 27.1/28.8 16.6/15.1
42.0/46.6 36.0/35.0 33.1/31.1 34.9/32.8 29.1/26.3 36.4/33.3 49.4/52.1 48.5/42.9 34.9/38.1 23.8/22.2 17.4/14.5 30.1/31.4 31.1/30.3
26.7/28.0 14.8/14.5 15.7/11.8 20.2/21.0 19.0/22.0 29.7/29.1 14.0/13.5 11.8/10.9 26.0/21.2 23.8/27.4 35.6/38.5 25.0/21.2 31.5/33.6
7.2/4.2 2.2/1.7 4.7/6.7 8.0/10.1 11.0/10.2 8.1/9.4 3.4/0.8 1.3/0.8 2.1/1.7 28.1/25.6 38.6/37.6 17.8/18.6 20.9/21.0
Burning feet is most frequently reported. SFN, small fiber neuropathy. *Data expressed as percentages of responders.
acceptable unidimensionality (0.055; 95% CI: 0.027–0.082). The item “brush your teeth” was the easiest item to perform, while “walk at least three flights of stairs” was the most difficult to accomplish (Fig. 2). The item difficulty ranged from −2.15 to 3.012 logits. Patient’s location ranged from −2.377 to 6.629 with 11.3% (27 of 238) having a maximum score.
the Pain-VAS and RT-SFN-SIQ© (Fig. 3). A significant trend was seen showing decreasing activity and participation ability of patients (lower SFN-RODS values) with increasing pain intensity and severity of SFN-related complaints (SFN-SIQ scores). The SFN-SIQ findings explained 26% of the SFN-RODS findings (p < 0.0001). Internal reliability for the final SFN-RODS© remained robust as indicated by a PSI of 0.91. Also, acceptable test-retest reliability scores were obtained for items’ weights and patients’ abilities (Fig. 4). The final SFN-RODS© and SFN-SIQ© are presented as Tables S1 and S2.
Rasch analyses of the SFN-SIQ© The 13 items were subjected to Rasch and almost all model’s expectations were directly met: item’s statistics: mean: 0.21, SD: 0.662; person’s statistics: −0.159; SD: 1.083, chi-square probability p = 0.80; unidimensionality was also met (two subsets of three items): proportion of significant t-tests: 0.046 (95% confidence interval: 0.018–0.074). PSI was also acceptable (0.77). None of the items had misfit statistics and their corresponding fit residuals fell within the allowed ±2.5 boundaries (Fig. S1). No local dependency and disordered thresholds were seen. No item bias was seen for all items except for “hot flashes” (uniform DIF) and “skin sensitivity of the legs” (non-uniform DIF) on person factor sex. These two items were split creating specific items for females and males, respectively. The statistics hardly changed: item’s statistics: mean: 0.131, SD: 0.735; person’s statistics: −0.151; SD: 1.074, chi-square probability p = 0.47; DF: 45. PSI remained unchanged (0.77). Therefore, to assure simplicity, the RT-SFN-SIQ data were used in the further analyses.
Discussion This paper presents two modern interval outcome measures, the SFN-RODS© and SFN-SIQ©, that fulfilled Rasch model expectations as part of a movement in improving the clinical assessment and care of patients suffering from SFN (Tennant and Conaghan, 2007). The SFN-SIQ© captures SFN-specific symptoms and the SFN-RODS© is the first interval measure specifically constructed to assess activity and participation restrictions in this condition. Acceptable validity and reliability values were also seen (good PSIs, see also Figs 3 and 4). In particular, increasing pain intensity (as captured with the VAS) and higher scores on the SFN-SIQ© (reflecting greater magnitude of symptoms) were related to a decrease in daily and social functioning (lower SFN-RODS© scores). The magnitude of neuropathic pain may lead to a diminished overall well-being and quality of life expectations, as
Validity and reliability studies The final 32-item SFN-RODS© scale demonstrated acceptable discriminative validity when correlated with 337
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Figure 2. Threshold map and item difficulty location for the final SFN-RODS©. Blue sections (0) = unable to perform; red sections (1) = able to perform, but with difficulty; green sections (2) = able to perform, without difficulty. A gradual shift is seen: the blue section of the item “able to brush your teeth” (the easiest item) is much shorter than the blue section of the item “able to walk at least 3 flights of stairs” (the most difficult items). The right panel presents the overall item difficulty locations for each item with the corresponding SE. RODS, Rasch-built overall disability scale; SFN, small fiber neuropathy.
Figure 3. (A) Association between SFN-RODS© and Pain-VAS. (B) Association between SFN-RODS© and SFN-SIQ©. A high patient location on the SFN-RODS© indicates a better activity and participation ability. With the increasing intensity of complaints present (as captured with the SFN-SIQ©) and higher pain scores, more activity and participation restrictions were seen. The mean pain VAS score of the cohort was 50.5 (SD: 27.3) and ranged from 0 to 100. NS, not significant; RODS, Rasch-built overall disability scale; SFN, small fiber neuropathy; SIQ, symptoms inventory questionnaire; VAS, Visual Analogue Scale.
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Figure 4. Test-retest reliability findings for the final SFN-RODS©. (A) Item difficulty hierarchy of the final SFN-RODS© in the first vs. the second assessment (interval 1 year). Almost all items (dots) were located within the 95% confidence interval (solid lines) reflecting ideal reliability. (B) Patients’ location in the first assessment vs. the second assessment. Most person scores (dots) were located within the 95% confidence interval (solid lines). RODS, Rasch-built overall disability scale; SFN, small fiber neuropathy.
has been reported previously (Poliakov and Toth, 2011; Bakkers et al., 2014). The development of the SFN-RODS© and transforming the SFN-SIQ© into an interval measure contribute to the pallet needed to evaluate the effect of SFN at all levels of assessing outcome, ranging from pathology (skin biopsy), to impairments (biophysical properties; SFN-SIQ©, pain assessment), to activity limitations and participation restrictions (newly developed SFN-RODS©), and to quality of life expectations (as demonstrated recently using the SF-36), which reflects the WHO framework of understanding the consequences of an illness (Ware et al., 2000; World Health Organization, 2001; Bakkers et al., 2009; Faber et al., 2012a; Hoeijmakers et al., 2012; Lauria et al., 2012). In addition, the Rasch-built SFN-RODS© and SFN-SIQ© outcomes also reflect a higher level of measurement precision, bypassing the known deficiencies of ordinal-based scales (Merbitz et al., 1989; Wright and Linacre, 1989; DeVellis, 2006). Some methodological issues related to this study should be addressed. First, the interval between the first and second assessment of the pre-phase SFN-RODS© was 1 year. It is conceivable that some patients may have experienced deterioration or even improvement, which may have influenced the reliability scores. However, most patients were located within the 95% confidence intervals, indicating a clinical unchanged status at the activity and participation level of assessing outcome (Fig. 3). Second, we have used the initial data for the SFN-SIQ© after subjecting these to Rasch analyses, as the scale demonstrated outstanding overall fit statistics from the first analysis. Only two items showed DIF. After splitting these two items, the statistics only change at the decimal levels. It is believed that these minor changes would not be of any influence on the correlations when compared to the data entry findings. Third, at the current stage, the responsiveness of the SFN-RODS©
and SFN-SIQ© has not been determined yet (Liang, 1995). Future interventional trials in SFN are needed to examine this. At the current stage, the assessment of pain should still be considered as the primary outcome in SFN, as has been suggested by the IMMPACT for all painful neuropathic studies (Dworkin et al., 2009). Fourth, SFN-related complaints not only have a large effect on quality of life expectations as recently reported by our group (Bakkers et al, 2014), but also on daily/social activities as shown in this study. However, these findings need validation in other SFN cohorts, as our patients were all Dutch. In conclusion, two disease-specific scales for SFN are presented: the RT-SFN-SIQ© assessing outcome at the impairment level and the SFN-RODS© that captures activity limitations and participation restrictions. Both scales have demonstrated good modern scientific soundness. Their use is therefore suggested in future clinical SFN trials to capture possible efficacy of an intervention.
Acknowledgements B. A. B., M. B., and J. G. J. H. were involved in recruitment, data collection, and preparation of the final report. C. G. F. and I. S. J. M. were involved in study design, statistical analysis, and preparation of the final report. B. A. B., M. B., and J. G. J. H. report no disclosures. C. G. F. reports grants from the European Union 7th Framework Program (grant number 602273), and the Prinses Beatrix Spierfonds (W.OR12-01). I. S. J. M. served on a scientific advisory board for CSL Behring, has received funding for travel from Talecris Biotherapeutics, and has received research support from the European Union 7th Framework Program (grant number 602273), the GBS/CIDP International Foundation, the Talents Program foundation, and the Peripheral Nerve Society. 339
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Supporting Information Additional Supporting Information may be found in the online version of this article.
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