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Validation and Banding of the ItchyQuant: A Self-Report Itch Severity Scale

Open ArchivePublished:August 10, 2016DOI:https://doi.org/10.1016/j.jid.2016.06.633
      Because of the significant emotional and psychosocial impact of chronic pruritus, it is important to accurately assess and measure itch severity. This study aims to validate and apply clinically meaningful bands to the ItchyQuant, an illustrated self-report numeric rating scale (NRS) for itch severity. A total of 76 adults with chronic pruritus were recruited. Participants rated their itch on the ItchyQuant, on a traditional 11-point NRS, and with verbal categorizations (no, mild, moderate, or severe). There was a significant, high correlation between the ItchyQuant and NRS (>0.92, P < 0.0001), demonstrating concurrent validity. Significantly more patients (47.2%) preferred the ItchyQuant than the NRS (23.6%) or had no preference (29.2%), P = 0.0015. Significantly more patients found the ItchyQuant easier to use (45.8%) than the NRS (20.8%) or had no preference (33.3%), P = 0.008. The set of clinically meaningful bands with the highest weighted kappa coefficient of agreement (κ = 0.69) was as follows: 0 (no itch), 1–3 (mild itch), 4–7 (moderate itch), 8–10 (severe itch). The ItchyQuant is a clinically meaningful measure of itch severity, demonstrating face and concurrent validity, that many patients prefer and find easier to use when compared with a traditional NRS. We suggest that the ItchyQuant can be added to the existing armamentarium of itch severity scales. We plan to investigate the ItchyQuant further in cognitively challenged populations.

      Abbreviations:

      NRS (numeric rating scale), REALM-SF (Rapid Estimate of Adult Literacy in Medicine-Short Form)

      Introduction

      Pruritus is ubiquitous in the population with an estimated point prevalence ranging from 13.5% to 16.7% and lifetime prevalence reaching 25% (
      • Matterne U.
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      Prevalence, correlates and characteristics of chronic pruritus: a population-based cross-sectional study.
      ,
      • Matterne U.
      • Apfelbacher C.J.
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      Incidence and determinants of chronic pruritus: a population-based cohort study.
      ). Pruritus does not simply accompany primary skin disease, but also can be a symptom of systemic disease or infectious disease (
      • Dawn A.
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      • Chan Y.H.
      • Rapp S.R.
      • Rassette N.
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      Itch characteristics in atopic dermatitis: results of a web-based questionnaire.
      ,
      • Kaushik S.B.
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      • et al.
      Chronic pruritus in HIV-positive patients in the southeastern United States: its prevalence and effect on quality of life.
      ,
      • Mela M.
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      Review article: pruritus in cholestatic and other liver diseases.
      ,
      • Rubenstein M.
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      Cutaneous manifestations of Hodgkin’s disease.
      ,
      • Weisshaar E.
      • Apfelbacher C.
      • Jäger G.
      • Zimmermann E.
      • Bruckner T.
      • Diepgen T.L.
      • et al.
      Pruritus as a leading symptom: clinical characteristics and quality of life in German and Ugandan patients.
      ). In many cases, the origin of pruritus remains unknown (
      • Sommer F.
      • Hensen P.
      • Böckenholt B.
      • Metze D.
      • Luger T.A.
      • Ständer S.
      Underlying diseases and co-factors in patients with severe chronic pruritus: a 3-year retrospective study.
      ,
      • Weisshaar E.
      • Apfelbacher C.
      • Jäger G.
      • Zimmermann E.
      • Bruckner T.
      • Diepgen T.L.
      • et al.
      Pruritus as a leading symptom: clinical characteristics and quality of life in German and Ugandan patients.
      ,
      • Zirwas M.J.
      • Seraly M.P.
      Pruritus of unknown origin: a retrospective study.
      ).
      The quality-of-life impact of pruritus is substantial, with increased rates of both depression and anxiety in patients with pruritus (
      • Schneider G.
      • Driesch G.
      • Heuft G.
      • Evers S.
      • Luger T.A.
      • Ständer S.
      Psychosomatic cofactors and psychiatric comorbidity in patients with chronic itch.
      ,
      • Zachariae R.
      • Lei U.
      • Haedersdal M.
      • Zachariae C.
      Itch severity and quality of life in patients with pruritus: preliminary validity of a Danish adaptation of the itch severity scale.
      ). These are on par with those of pain, such that measures have shown that patients with chronic pruritus would be willing to sacrifice 13% of their life expectancy to be pruritus free (
      • Chen S.C.
      Pruritus.
      ,
      • Kini S.P.
      • DeLong L.K.
      • Veledar E.
      • McKenzie-Brown A.M.
      • Schaufele M.
      • Chen S.C.
      The impact of pruritus on quality of life: the skin equivalent of pain.
      ). The annual direct cost of managing chronic pruritus in the setting of atopic dermatitis, a disease defined by pruritus, was approximately $364 million in 1990 (
      • Ellis C.N.
      • Drake L.A.
      • Prendergast M.M.
      • Abramovits W.
      • Boguniewicz M.
      • Daniel C.R.
      • et al.
      Cost of atopic dermatitis and eczema in the United States.
      ,
      • Lapidus C.S.
      • Schwarz D.F.
      • Honig P.J.
      Atopic dermatitis in children: who cares? Who pays?.
      ). For third-party payers, the annual costs for chronic pruritus are similar to those for emphysema and epilepsy (
      • Carroll C.L.
      • Balkrishnan R.
      • Feldman S.R.
      • Fleischer A.B.
      • Manuel J.C.
      The burden of atopic dermatitis: impact on the patient, family, and society.
      ). Because of the significant emotional, psychosocial, and economic burden secondary to chronic itch, it is important to be able to accurately assess and measure the severity of itch to guide proper management and treatment.
      Multiple unidimensional patient-rating scales of pruritus severity have been evaluated, including numeric rating scales (NRS), visual analog scales, and verbal rating scales. High correlation between these scales has been shown, and the psychometric properties of these itch severity scales, including concurrent validity and reliability, have been demonstrated (
      • Phan N.Q.
      • Blome C.
      • Fritz F.
      • Gerss J.
      • Reich A.
      • Ebata T.
      • et al.
      Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus.
      ,
      • Reich A.
      • Heisig M.
      • Phan N.Q.
      • Taneda K.
      • Takamori K.
      • Takeuchi S.
      • et al.
      Visual analogue scale: evaluation of the instrument for the assessment of pruritus.
      ). Clinical bands have been defined to represent clinically meaningful categorization of itch severity on the visual analog scale as well (
      • Reich A.
      • Heisig M.
      • Phan N.Q.
      • Taneda K.
      • Takamori K.
      • Takeuchi S.
      • et al.
      Visual analogue scale: evaluation of the instrument for the assessment of pruritus.
      ).
      Although these existing tools have been shown to be both reliable and valid in the itchy adult population, studies have indicated that use of the visual analog scale may not be suitable in individuals who have age-associated cognitive limitations, including the elderly and young children (
      • Reich A.
      • Heisig M.
      • Phan N.Q.
      • Taneda K.
      • Takamori K.
      • Takeuchi S.
      • et al.
      Visual analogue scale: evaluation of the instrument for the assessment of pruritus.
      ), or in individuals for whom English was not their first language. We will henceforth refer to these populations as populations with cognitive limitations.
      This concern is also echoed in pain severity measurement (
      • Peters M.L.
      • Patijn J.
      • Lamé I.
      Pain assessment in younger and older pain patients: psychometric properties and patient preference of five commonly used measures of pain intensity.
      ). Researchers developed illustrated self-report “faces scales” for children, such as the Faces Pain Scale and Wong-Baker FACES pain scale, to address the need for scales that can be used for children who were unable to adequately map their pain onto a two-dimensional numeric scale (
      • Bieri D.
      • Reeve R.A.
      • Champion G.D.
      • Addicoat L.
      • Ziegler J.B.
      The Faces Pain Scale for the self-assessment of the severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio scale properties.
      ,
      • Garra G.
      • Singer A.J.
      • Taira B.R.
      • Chohan J.
      • Cardoz H.
      • Chisena E.
      • et al.
      Validation of the Wong-Baker FACES Pain Rating Scale in pediatric emergency department patients.
      ,
      • Hicks C.L.
      • von Baeyer C.L.
      • Spafford P.A.
      • van Korlaar I.
      • Goodenough B.
      The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement.
      ,
      • von Baeyer C.L.
      Children’s self-report of pain intensity: what we know, where we are headed.
      ). To the best of our knowledge, no such scales are widely used for the measurement of itch severity in dermatology. There is one illustrated itch scale, the Itch Man, but it utilizes unrealistic box-like cartoons and has not been investigated outside of the setting of pediatric burns (
      • Morris V.
      • Murphy L.M.
      • Rosenberg M.
      • Rosenberg L.
      • Holzer C.E.
      • Meyer W.J.
      Itch assessment scale for the pediatric burn survivor.
      ).
      In response, our group has developed ItchyQuant, a self-reported, illustrated NRS for the severity of itch. Unlike other pruritus scales, the ItchyQuant incorporates cartoon depictions of the various severities of itch. This multisite study seeks to validate the ItchyQuant in adults without evident cognitive impairments, so it can later be applied to the aforementioned populations with cognitive limitations where we believe that the scale will have the most clinical utility.

      Results

      Population

      A total of 76 of 82 subjects chose to participate (response rate 92.7%) across all sites (Emory, n = 22 [29%], Rush, n = 19 [25%], OHSU, n = 18 [24%], Temple, n = 17 [22%]). Fifty-one percent of subjects were male. The average age of subjects was 52.8 ± 17.9 years. Subjects self-identified race as white/Caucasian (57%), black/African American (24%), Hispanic/Latino (11%), East Asian/Pacific Islander (5.2%), American Indian (0%), South Asian (0%), or other (4%). A total of 54% of subjects started or completed undergraduate coursework, 28% had pursued postcollege or graduate education, and 18% had completed high school or less. Ninety-one percent of subjects spoke English as their first language. Seventy-five percent of subjects had Rapid Estimate of Adult Literacy in Medicine-Short Form (REALM-SF) scores equivalent to 9th grade or greater, followed by 7th–8th grade (18%) and 4th–6th grade (7%). The most powerful medications used for pruritus treatment at the time of recruitment were systemic immunosuppressants (24%), high-potency topical steroids (27%), and low-potency topical steroids (13%). Many patients did not use steroids; 5% of patients used over-the-counter medications such as antihistamines, 7% used only using over-the-counter emollients, and 8% of patients were not using any medications for pruritus. One patient did not report current medications. Etiology of pruritus was skin related in 50% of patients, unknown in 38%, and from systemic illness or a combination of systemic and skin related in 12%.

      Concurrent validity

      There was a significant, high correlation between the ItchyQuant and NRS (r > 0.92, P < 0.0001), demonstrating concurrent validity between the scales. The power for this correlation was >0.999.

      Scale ease and preference

      Significantly more patients (47.2%) preferred the ItchyQuant than preferred the NRS (23.6%) or had no preference (29.2%), P = 0.0015. Additionally, significantly more patients found the ItchyQuant easier to use (45.8%) than the NRS (20.8%) or had no preference (33.3%), P = 0.008.
      Of the 25 patients who gave their reasons for preferring or finding the ItchyQuant easier to use, 88% stated the ItchyQuant allowed for better visual representation and illustrative description of itch severity. Of the 11 patients who gave their reasons for preferring the NRS, 45% stated the NRS simpler and clearer.

      Predictors of scale preference

      Multivariate regression analysis showed that age significantly predicted scale preference (β = −0.02, P = 0.0021). This signifies that patients’ preference for the ItchyQuant decreased with every 0.02 years their age increased. Neither gender nor REALM-SF score significantly predicts scale preference.

      ItchyQuant bands

      A strong correlation between the verbal itch categorization and ItchyQuant was shown (0.82, P < 0.0001). The unweighted and weighted kappa coefficients of agreement for the four sets of ItchyQuant bands that were constructed are shown in Table 1. The band set with the highest unweighted and weighted kappa coefficients of agreement (κ = 0.64, 0.69) is as follows: 0 (no itch), 1–3 (mild itch), 4–7 (moderate itch), 8–10 (severe itch).
      Table 1ItchyQuant band sets: potential band sets (A–D) with corresponding unweighted and weighted kappa coefficients of agreement
      Band 1 (no itch)Band 2 (mild)Band 3 (moderate)Band 4 (severe)Unweighted kappaWeighted kappa
      Set A01–45–78–100.560.63
      Set B01–45–67–100.440.54
      Set C01–34–67–100.520.60
      Set D01–34–78–100.640.69

      Discussion

      Pruritus is a subjective phenomenon, the intensity of which is difficult to objectively measure. Many self-reported scales used to quantify itch severity have been assessed and shown to be both valid and reliable (
      • Phan N.Q.
      • Blome C.
      • Fritz F.
      • Gerss J.
      • Reich A.
      • Ebata T.
      • et al.
      Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus.
      ). However, to our knowledge, no scale that utilizes pictorial descriptions of itch severity has been assessed within the field of dermatology. We have developed the ItchyQuant to address this gap. Given the lack of a gold standard measurement tool for itch severity, we compared the ItchyQuant with the traditional NRS, the psychometric properties of which have already been demonstrated in an adult population without cognitive limitations (
      • Phan N.Q.
      • Blome C.
      • Fritz F.
      • Gerss J.
      • Reich A.
      • Ebata T.
      • et al.
      Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus.
      ). Our study identifies high concurrent validity of the ItchyQuant with this traditional NRS and fulfills face validity. Additionally, if we combine the proportion of subjects who preferred the ItchyQuant with those who had no preference, the NRS-preferred proportion is very small (29.2% vs. 70.8%). Patients who preferred the ItchyQuant stated that their preference stemmed from the “illustrative” and “more descriptive” nature of cartoons. For both reasons, we suggest that the ItchyQuant is at least equivalent to NRS in assessing itch severity in this English-speaking cognitively intact population.
      We expect an even higher preference for the ItchyQuant in individuals with non-English as their first language and geriatric populations, but especially the pediatric populations given our findings of a statistically significant, albeit not clinically significant, relationship existing between age and scale preference, with younger age preferring the ItchyQuant. The patient REALM-SF health literacy score and gender did not predict scale preference. The lack of the predictive effect of the REALM-SF score on scale preference likely stems from the high health literacy of our study population, as 75% of patients had the highest REALM-SF score possible. All of these factors and opinions must be considered when selecting the scale to be used in a specific clinical setting.
      Arguably, the most important use of a scale is showing that it can be clinically meaningful and help aid in the management of patients. This clinical utility can be demonstrated through applying clinically meaningful bands to the scale. We utilized the banding techniques set forth in
      • Hongbo Y.
      • Thomas C.L.
      • Harrison M.A.
      • Salek M.S.
      • Finlay A.Y.
      Translating the science of quality of life into practice: what do dermatology life quality index scores mean?.
      and
      • Love E.M.
      • Marrazzo G.A.
      • Kini S.
      • Veledar E.
      • Chen S.C.
      ItchyQoL bands: pilot clinical interpretation of scores.
      to apply itch severity categorizations to the ItchyQuant. Results of this analysis showed that the ItchyQuant can be banded to delineate four different categories of itch severity (no, mild, moderate, or severe itch) in a way that proves clinically meaningful. Application of these bands to the ItchyQuant allows users to better describe and assess a patient’s response to treatment and determine whether changes in itch severity rating are clinically significant rather than simply statistically significant. Interestingly, these clinical bands correspond well to the clinical bands applied to the visual analog scale by
      • Reich A.
      • Heisig M.
      • Phan N.Q.
      • Taneda K.
      • Takamori K.
      • Takeuchi S.
      • et al.
      Visual analogue scale: evaluation of the instrument for the assessment of pruritus.
      .
      Questions regarding whether or not the cartoon figures in the ItchyQuant were being used as response choices rather than anchors or guides were raised during this study. We feel confident that each individual did not simply use the cartoons as a response choice, but instead used the cartoons as anchors to guide and inform their numerical selection on the severity scale. Additionally, we did not need to use verbal descriptions in conjunction with the cartoons to explain the illustrations to the subjects. However, we recognize that the description of each individual cartoon might prove to be necessary in other patient populations. In response, we have developed a working script for our recently started study of the ItchyQuant in the pediatric population. This script can be viewed in Supplementary Materials online.
      The ItchyQuant can be used alone or in combination with other measures to evaluate pruritus in various skin diseases. ItchyQuant is a unidimensional tool that focuses solely on self-reported itch severity. Thus, it complements quality-of-life instruments, which are multidimensional instruments that delve in depth into the various aspects of how a disease (or symptom) affects the individual. It is notable that the ItchyQoL was developed to be used regardless of the etiology of the pruritus. Thus, it can be used with existing scales that assess objective signs of severity such as the Eczema Area and Severity Index or the Psoriasis Area Severity Index. There are a few disease severity indices, such as the SCORing Atopic Dermatitis (SCORAD), that do include self-rated pruritus severity. However, the SCORing Atopic Dermatitis (SCORAD) does not utilize a cartoon-annotated scale, and thus would not be able to be used in a population that may not understand a nonannotated NRS. The ItchyQuant is not necessary for use with SCORAD in patients who understand the NRS. The ItchyQuant, once validated, would be useful in conjunction with SCORAD in the more cognitively challenged populations.
      Of note, the cognitively intact, English-speaking adult group in this study is not the target population that would most benefit from the ItchyQuant. Such adults can use other self-reported itch severity scales. We believe that the cartoon-annotated ItchyQuant is most needed in individuals with age-related cognitive limitations or non-English as their first language. We did not, however, investigate the feasibility and validity of the use of the scale in these populations initially because it made most sense to test in an already well-studied, fairly predictable, patient population. If the ItchyQuant had not shown high concurrent validity in cognitively intact English-as-a-first-language adults, there would be little point to then test it in individuals with age-associated cognitive limitations or non-English as their first language. Now that our data suggest that the ItchyQuant is valid and acceptable in the first population, we feel confident to proceed with a study of the scale in the other population such as pediatrics, geriatrics, and nonprimary English speaking.
      We note multiple potential limitations to the current study including a lack of heterogeneity in patient health literacy and a small study population size. Although the study population size was small, we believe that the very strong correlation was shown between the ItchyQuant and NRS, and power of the correlation gives strong evidence to support the further study of the tool in other populations. A large number of patients included in this study were using powerful systemic immunosuppressants and high potency topical steroids, which might not reflect the more general itchy population. Further testing in a more heterogeneous population is needed. We also recognize that more psychometric testing will be needed once we investigate the use of the ItchyQuant in other populations, such as cross-cultural validity.
      We also recognize potential limitations of the current version of the ItchyQuant that are specific to the pediatric population. The cartoon characters on the scale are male and could potentially cause confusion for female children who might not be able to relate to the scale given the difference in gender. Furthermore, the characters on the ItchyQuant scale are scratching different areas of their bodies and have rashes on their skin. Children who have itchy skin in locations other than those depicted in the cartoons, or children who do not have a rash accompanying their itchy skin, might not be able to extrapolate their own itch severity using the scale. These potential problems did not occur in adults; however, we are aware of these issues as we move to looking at the use of ItchyQuant in pediatric populations in the future.
      There are also clinical settings where the utility of the ItchyQuant is limited. The scale could not be used over the phone, as the patient would be unable to view the illustrations. The use of the scale in conjunction with previously established electronic medical record platforms could also become a problem, as the scale is not integrated into these systems.
      In summary, itch severity scales complement other tools such as quality-of-life measures and disease severity measures. The ItchyQuant is a cartoon-annotated single-item measure of itch severity that demonstrates concurrent and face validity, and that patients both prefer and find easier or equivalent to use when compared with a traditional NRS. We do not presume this scale to be superior to previously validated severity scales in a population of adults without cognitive limitations, but rather it joins an existing set of tools that are currently available for the adult population without cognitive limitations. We instead suggest its potential utility in patients with more limited cognition or understanding. The use of this scale needs to be evaluated further in these populations, particularly the pediatric population, where it could prove most useful.

      Materials and Methods

      Procedure

      Adults, aged 18 or older, with a history of chronic pruritus, or itch lasting greater than 6 weeks, were recruited from dermatology clinics at Rush University, Temple University, Oregon Health and Science University, and Emory University between November 2014 and June 2015. Exclusion criteria included the inability to speak or understand English. Institutional review board approval was obtained at each center, and written informed consent was obtained from all patients.
      Patients were asked to rate their pruritus severity over the last 7 days on a traditional 11-point NRS and on the ItchyQuant. Each scale was administered at either the beginning or end of the clinic visit. Order of administration was randomized by patient and clinical site using a random number generator. Patients were additionally asked to categorize or rate their itch over the last 7 days as either no itch, mild itch, moderate itch, or severe itch. We will refer to this process as their verbal itch categorization. Basic demographic information, body areas affected by itch, and current medications were recorded. Patients were asked to self-report race/ethnicity from a list provided. Patient health literacy was assessed with the REALM-SF, a 7-item word recognition test (
      • Arozullah A.M.
      • Yarnold P.R.
      • Bennett C.L.
      • Soltysik R.C.
      • Wolf M.S.
      • Ferreira R.M.
      • et al.
      Development and validation of a short-form, rapid estimate of adult literacy in medicine.
      ).

      The scales

      Numeric rating scale

      The traditional 11-point NRS ranges from 0 to 10, with 0 being no itch and 10 being the worst itch imaginable (Figure 1a).
      Figure 1
      Figure 1Rating scales used in study. (Top) Numeric rating scale. Traditional 11-point numeric rating scale used in this study, with 0 representing no itch and 10 representing the worst itch imaginable. (Bottom) The ItchyQuant. Illustrated 11-point pruritus rating scale used in this study, with 0 representing no itch and 10 representing the worst itch imaginable.

      ItchyQuant

      The ItchyQuant is a self-report itch severity scale based on the traditional 11-point NRS that incorporates cartoon pictures to better describe itch severity. The cartoons depict various severities of itch by the changing facial expression and amount of scratching. It also ranges from 0 to 10, with 0 being no itch and 10 being the worst itch imaginable (Figure 1b). The scale is anchored at 0 with a character who is not itchy and also at 10 with a character representing the “worst itch imaginable.”

      Statistical analysis

      All statistical analysis was done in SAS 9.3. We considered a P value < 0.05 as statistically significant.

      Concurrent validity

      Concurrent validity measures how well a certain measurement of a construct correlates with a previously validated measure of the same construct (
      • Punch K.F.
      Introduction to social research: quantitative and qualitative approaches.
      ). Pearson correlation coefficients between the ItchyQuant and NRS were calculated to evaluate concurrent validity. The NRS was used for comparison given its validation by
      • Phan N.Q.
      • Blome C.
      • Fritz F.
      • Gerss J.
      • Reich A.
      • Ebata T.
      • et al.
      Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus.
      .

      Scale preference and ease

      A Wilcoxon signed rank test was used to determine statistically significant differences in patient opinion of which scale they preferred and found easier to use. The reasons for their choice were recorded.

      Predictors of scale preference

      Multivariate regression analysis was performed to determine if the REALM-SF health literacy score, age, or gender had a statistically significant effect on scale preference.

      ItchyQuant bands

      The procedure for banding of the ItchyQuant was adapted from
      • Hongbo Y.
      • Thomas C.L.
      • Harrison M.A.
      • Salek M.S.
      • Finlay A.Y.
      Translating the science of quality of life into practice: what do dermatology life quality index scores mean?.
      and
      • Love E.M.
      • Marrazzo G.A.
      • Kini S.
      • Veledar E.
      • Chen S.C.
      ItchyQoL bands: pilot clinical interpretation of scores.
      . The Pearson correlation coefficient was estimated between patient verbal itch categorization and ItchyQuant itch severity rating. The mean, median, and mode ItchyQuant score corresponding to each category of the verbal itch categorization were calculated. Using these values, four potential ItchyQuant band sets were generated in an attempt to evenly distribute each ItchyQuant score within the bands with as little overlap as possible. The kappa coefficient of agreement was calculated for each of the four sets of ItchyQuant bands. The band set with the highest kappa value was adopted as the best banding for the ItchyQuant.

      Conflict of Interest

      SCC will receive future royalties from the ItchyQuant. All other authors state no conflict of interest.

      Acknowledgments

      We are indebted to Carmen Petrizzo and Danica Uzelac for their aid in this project.

      Supplementary Material

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