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NDT Advance Access published online on September 17, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn523
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Psychometric evaluation of the National Kidney Dialysis and Kidney Transplantation Study symptom checklist: reliability and validity

David M. Spiegel1, Roger W. Evans2, Matthew Gitlin3 and Tracy J. Mayne3

1 University of Colorado Denver Health Sciences Center, CO 2 Evans Health, MN 3 Amgen, Inc., CA, USA

Correspondence and offprint requests to: David M. Spiegel, 4545 E. 9th Ave, Suite 160, Denver, CO, 80220. Tel: 303-399-6997; Fax: 303-399-3131; E-mail: david.spiegel{at}uchsc.edu



   Abstract
Top
 Abstract
Introduction
 Original development and...
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Background. Patient-reported outcomes (PROs) are critical in the evaluation of treatment effectiveness. The National Kidney Dialysis and Kidney Transplantation Study (NKDKTS) symptom checklist was developed in the 1980s as a means to better understand the relationships amongst end-stage renal disease (ESRD), anaemia symptoms and multiple quality of life indicators. Unfortunately, key components of validity and reliability were not established at the time of the study. The present study helps fill this void by evaluating the psychometric properties of the 13-item NKDKTS symptom checklist, a measure of anaemia symptom frequency, in a dialysis population.

Methods. The NKDKTS symptom checklist was administered to 104 dialysis patients in three dialysis units at baseline, 48 h and 7 days. Internal consistency, test–retest reliability and construct validity via known-groups responsiveness were evaluated.

Results. Principal components factor analyses produced a single factor at each time point, with all items loading >0.50 across time points, and accounting for 37%, 44% and 46% of the variance at each time point (respectively). Forcing a 2-factor solution across time points yielded a single instance of an item loading more highly on factor 2 (0.57) than on factor 1 (0.53). Internal consistency was good at all three time points (Cronbach's alpha = 0.86, 0.89 and 0.90, respectively). Known-groups validity was evaluated by examining the symptom scores of subjects categorized by haemoglobin level. Subjects with lower haemoglobin levels reported significantly more symptoms, and the point estimates and variance at each haemoglobin level were stable over time.

Conclusion. The results of this study provide further evidence supporting the validity and reliability of the NKDKTS symptom checklist.

Keywords: anaemia; dialysis; health-related quality of life; reliability; symptoms



   Introduction
Top
 Abstract
 Introduction
Original development and...
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Over 450 000 Americans live with end-stage renal disease (ESRD) of which ~350 000 receive dialysis [1]. For patients with chronic kidney disease (CKD), the kidney's inability to regulate the production of red blood cells through the release of erythropoietin results in progressively worsening anaemia [2]. Currently, anaemia is managed by supplementing residual endogenous erythropoietin with erythropoietin stimulating agents (ESAs), or in cases of acute severe anaemia with blood transfusion [3]. Established consensus guidelines for transfusion indicate that anaemia symptoms, along with haemoglobin level, define the need for administering red blood cell transfusion [4–6].

At its most basic level, anaemia is a lack of sufficient haemoglobin, the molecule that carries oxygen to the body's tissues. At low enough haemoglobin levels, oxygen delivery cannot meet the body's demands and tissues become hypoxic, unable to function and in extreme cases resulting in death. The perception of hypoxia is related to the tissue being affected, such that muscle hypoxia is perceived as weakness or pain whereas more generalized hypoxia may be perceived as shortness of breath or low energy level. However, there is rarely a one-on-one correspondence between biomarker measures and patient-reported symptoms, as patient reporting is affected by many factors. Patients can be more or less sensitive to changes in their physical state, and are influenced by social norms and social desirability when reporting symptoms [7,8]. Because patient-reported anaemia symptoms are vital to anaemia management, it is important to have a valid and reliable instrument for measuring these symptoms, and to understand the relationship of these symptoms to changes in haemoglobin level, and ultimately as a signal for the need to medically intervene. Beyond their importance as part of this clinical decision-making process, patient-reported disease-related symptoms are critical components for evaluating treatment effects from the patient's perspective [9]. Disease-related symptoms can be measured along two pathways, symptom occurrence that is measured in terms of frequency or severity, and symptom distress, which encompasses mental anguish or suffering caused by a specific symptom. The research questions guiding this study were: 1) Is the measurement of symptom frequency assessed by the National Kidney Dialysis and Kidney Transplantation Study (NKDKTS) symptom scale sensitive to within- and between-patient differences in haemoglobin, and 2) does it reliably measure those differences over time?

A review of the literature identified one instrument that had been used in large studies of ESRD patients as well as randomized controlled trials of anaemia treatments in this population: the NKDKTS symptom checklist [10–12]. This questionnaire assesses the frequency of anaemia symptoms that previous validation research demonstrated are bothersome to patients with ESRD. Although the literature included some validation information on this instrument, reliability and responsiveness have not been established, and validity specific to haemoglobin levels and anaemia remains unclear. The NKDKTS symptom checklist's ability to evaluate anaemia symptoms may provide a more efficient method of identifying current and future changes in disease status, specifically related to declines in haemoglobin levels that may help to improve patient prognosis, and in conjunction with other patient-reported outcome (PRO) measures such as the Kidney Disease Questionnaire or Kidney Disease Quality of Life Questionnaire provide a full picture of the impact of anaemia on patients' health-related quality of life. Therefore, the objective of this study was to assess the reliability, validity and responsiveness of the NKDKTS symptom checklist in ESRD patients undergoing dialysis, specifically linking symptom frequency to levels of anaemia as measured by blood haemoglobin.



   Original development and validation of the NKDKTS symptom checklist
Top
 Abstract
 Introduction
 Original development and...
Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Evans et al. (1987) developed the NKDKTS symptom checklist [13–15]. The checklist was based on 16 domains identified and validated in the 1978 Survey of Disability and Work and National Health Interview Survey (NHIS) [13]. Evans et al. used the 16 domains to create an initial set of items for the NKDKTS symptom checklist (see Table 1) [13]. The NKDKTS was a large, multicentre observational study of 859 subjects with ESRD who were on dialysis (in-center hemodialysis, home hemodialysis, peritoneal dialysis) or who had received a kidney transplant. As part of the study, subjects were read the 16 symptoms and asked, in a yes/no format, whether each symptom had ‘bothered them enough to be a problem in the past month’. From this and subsequent cognitive debriefing interviews, a shorter symptom frequency checklist was developed based on a subset of eight items as being relevant to subjects with ESRD receiving dialysis. These symptoms included tiring easily/no energy; weakness/lack of strength; shortness of breath/trouble breathing; fainting spells/dizziness; aches/swelling/sick feeling; nervousness/tension/anxiety; depression and pain.


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  		Table 1 Sixteen domains identified in the Survey of Disability and Work to create an initial set of items for the NKDKTS symptom checklist [10]

 
The results of the 1987 NKDKTS showed good discriminant validity for six of the eight items in distinguishing between patients on hemodialysis versus those who had received a kidney transplant. As shown in Table 2, patients who had received transplants (average time since transplant was 4.28 years) reported significantly fewer symptoms than patients on hemodialysis, with the exception of nervousness/tension/anxiety and depression. It is worth noting that this study pre-dated the approval and use of Epoetin alfa.


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  		Table 2 Symptom report in hemodialysis and kidney transplant patients from the NKDKTS (Evans et al., 1987) [13]

 
Having identified symptoms that were bothersome for patients, and which discriminated between ESRD patients on dialysis versus those who had received renal transplant, a 13-item NKDKTS symptom checklist was developed to measure symptom frequency, for use in clinical trials of ESRD-related anaemia that were part of the Epoetin alfa clinical trial program [11,12,14]. Based on the results of patient feedback from phase II trials, the investigators added an additional five items to the eight identified in the NKDKTS, as relevant to anaemia: tremors, muscle weakness, leg cramps, muscle spasms and shaky hands. The recall period for the questionnaire was 2 weeks. The response set had patients’ rate symptoms on a 4-point frequency scale, ranging from ‘Never’ and ‘Rarely’ to ‘Sometimes’ and ‘Often’. A recent Bayesian meta-analysis of these trial results showed that, with the exception of nervousness/anxiety/tension, tremor and muscle spasms, all symptoms in this RCT version of the NKDKTS symptom checklist had a >70% probability of improving with Epoetin alfa treatment relative to placebo [16]. The presumptive mediating mechanism in these studies was the statistically significant increase (P < 0.001) in haemoglobin resulting from treatment with Epoetin alfa.

To provide additional validation that the items in the RCT version of the NKDKTS symptom checklist reflect anaemia symptoms, as opposed to ESRD or dialysis more generally, we reviewed anaemia symptoms as presented in National Anaemia Guidelines [11–13,17–21]. The results are shown in Table 3. As shown, seven items appeared in at least one anaemia guideline and three others were included in phase II patient feedback from anaemia trials. Three items did not appear in either the anaemia guidelines or the phase II trials.


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  		Table 3 Symptoms of anaemia defined by leading physician and patient organizations and identified by patients in clinical trials

 


   Materials and methods
Top
 Abstract
 Introduction
 Original development and...
 Materials and methods
Results
 Discussion
 Conclusion
 References
 
This was a prospective, observational study of 104 ESRD patients receiving hemodialysis at three dialysis clinics in the western USA. Patients were included who were
  1. ≥18 years of age,
  2. scheduled to receive hemodialysis three times per week between 15 August 2007 and 30 August 2007,
  3. receiving recombinant human erythropoietin and
  4. were able to speak and understand English to the degree necessary to provide informed consent and complete the questionnaire.

Patients were approached by research staff and asked to participate. They received a full description of the study and staff answered any and all questions. Those who were willing to participate completed and received a copy of the informed consent approved by the University of Colorado Multi-Institutional Review Board. The patients who provided informed consent underwent a chart review to collect the following demographic and medical information:

  1. Demographics: age, gender, race/ethnicity, highest education level;
  2. Medical History: years on dialysis, Hx diabetes, Hx hypertension, Hx of cardiovascular events;
  3. Most recent laboratory values: TSAT, ferritin, PTH, Kt/V.

Before initiating dialysis on either Wednesday or Thursday, patients completed the RCT version of the NKDKTS symptom checklist. After the patients were prepared to begin dialysis, ~4 cc of blood was drawn pre-dialysis from the dialysis needle. The blood samples were packaged as biohazard and transported to the University Hospital central laboratory for analysis of haemoglobin concentration.

Patients completed the RCT version of the NKDKTS symptom checklist, and 4 cc of blood was drawn again when the patients returned for dialysis treatment 48 h and 7 days after the baseline data were collected.

Statistical methods
All subjects who completed the baseline survey were included in the validation analysis. To the extent possible, the FDA's draft guidance document was followed for evaluating the psychometric properties that should be established for a PROs questionnaire to support labeling claims or for promotional purposes [9].

Subject demographic and clinical characteristics
Demographic and clinical characteristics were described by computing frequency distributions of the categorical variables for each characteristic.

Scaling
To ascertain the structure of the NKDKTS symptom checklist, we conducted principal components factor analyses. Given the single factor structure (as shown in the Results section), no rotation matrix was applied.

Variability
We examined the variability of the NKDKTS symptom checklist items and scale at each assessment. Floor and ceiling effects were assessed by examining the percent of subjects who had the lowest and the highest possible scale score across assessments.

Reliability
Internal consistency, the extent to which items or scales are measuring the same concept, was assessed using Cronbach's alpha [22,23]. Cronbach's alpha, and Cronbach's alpha with each item removed, was computed at each time point. An alpha coefficient ≥0.70 was considered to represent acceptable reliability [24].

To evaluate the stability of an instrument, it is recommended that it be tested in the target population-based on a test–retest design [25]. Test–retest reliability is often computed as an intraclass correlation coefficient, which compares the variability of different ratings of the same subject to the total variation across all ratings and all subjects. We computed intraclass correlation (using a one-way random model) from baseline to 48 h.

Validity
Known-groups validity evaluates the ability of the measure to discriminate between groups known to be clinically different. Known-groups validity was assessed using an analysis of variance (ANOVA) to compare NKDKTS symptom checklist scale scores of subjects at four haemoglobin levels: <10 g/dL; 10–12 g/dL; >12–13 g/dL and >13 g/dL. These haemoglobin levels were chosen as those relevant to treating physicians, based on the Epoetin alfa US label for the treatment of anaemia as well as the Kidney Disease Outcomes Qualitative Initiative (KDOQI) anaemia treatment guidelines of the National Kidney Foundation. In dialysis patients, haemoglobin levels <10 g/dL represent significant anaemia and require correction. The optimum range of haemoglobin in dialysis patients is 10–12 g/dL, though natural variability can result in haemoglobin levels in the 12–13 g/dL range. Haemoglobin levels >13 g/dL are to be avoided. The most important differentiation for clinicians would be the symptom levels <10 g/dL, and those within the recommended range of 10–12 g/dL. Previous studies have shown a linear relationship between haemoglobin and health-related PROs [26–28], and we a priori hypothesized that lower haemoglobin would be associated with greater anaemia symptoms. Therefore, we computed the ANOVA with linear contrasts. We conducted separate ANOVAs for baseline, 48 h and 7 days. To further characterize the cross-sectional relationship between NKDKTS symptom scores and haemoglobin levels, we ran univariate regression analyses, reporting the r, R2, intercept and B.

Responsiveness
Responsiveness measures how effectively the questionnaire detects change. Normally, this would be evaluated correlating change from baseline in the measure of interest versus change in a clinical variable (in this case, the NKDKTS symptom scale score versus haemoglobin). Responsiveness is also assessed using Guyatt's statistic, comparing patients whose scores on a measure are unchanged versus those whose scores have changed [29]. In this sample of treated ESRD patients, the change in haemoglobin over a 1-week period showed very little variation: the median change was 0, and the mean was 0.09. Only three patients had a change in haemoglobin >+1 g/dL, and only two patients had a change <–1 g/dL. The lack of change in the clinical parameter does not permit a formal responsiveness analysis.

All statistical analyses were generated using SPSS® Software, Version 14.0 of the SPSS System for Windows.



   Results
Top
 Abstract
 Introduction
 Original development and...
 Materials and methods
 Results
Discussion
 Conclusion
 References
 
Subject demographic and clinical characteristics
Of 195 patients seen at the dialysis units, 82 did not meet eligibility criteria. Of the 113 patients approached, 9 refused to participate. The primary reason for lack of participation was ‘did not want to be bothered’ or lack of trust in the purpose and use of the study.

Table 4 summarizes the demographic and clinical characteristics of the 104 ESRD patients who completed the baseline assessment. The majority were male (54%), and the largest racial group was Black/African American (41%). The mean age was 58 ± 15 years. The majority of patients had diabetes and/or hypertension, and nearly half had a history of cardiovascular disease (45%).


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  		Table 4 Demographic and clinical characteristics

 
Factor structure
Principal components factor analyses at all three time points showed a stable, single factor structure with all items positively weighted >0.50 (Table 5). This single factor accounted for 37%, 44% and 46% of the variance at each time point, respectively. We imposed a 2-factor solution at each time point. With one exception, all items loaded more highly on factor 1 than factor 2 at each time point (data not shown). The exception was item 1 (pain) that loaded slightly higher on factor 2 (0.57) than factor 1 (0.53) at the first time point only. The factor structure of the second factor was not stable over time, with large differences in absolute value and direction of loading. The incremental variance explained by a second factor was 12% at baseline, 13% at 48 h and 11% at 7 days.


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  		Table 5 NKDKTS symptom checklist unrotated factor 1 weights at baseline, 48 h and 7 days; and intraclass correlation (ICC) for baseline versus 48 h

 
Variability
The NKDKTS scale and individual items demonstrated good and stable variability. The mean ± SD scale score was 37 ± 8 at baseline, 38 ± 8 at 48 h and 38 ± 8 at 7 days. The distribution was normal, with a slight negative skew (skewness = –0.3, –0.2, –0.3, respectively). No patients reported a maximal symptom score (a score of 13) at any visit, indicating that there was no ceiling effect. A small number of patients (two at baseline, four at 48 h and four at 7 days) reported having no symptoms (a score of 52). Only one patient reported no symptoms at all three visits. Thus, there was very minimal basement effect.

Internal consistency reliability
Internal consistency, as measured by Cronbach's alpha coefficient, was good: 0.86 at baseline, 0.89 at 48 h and 0.90 at 7 days. Across all three time points, Cronbach's alpha coefficient decreased if any individual item was deleted.

Test–retest reliability
Intraclass correlations from baseline to 48 h ranged from 0.59 to 0.82, and were statistically significantly different for zero at P < 0.0001.

Known-groups validity
Known-groups validity was conducted using summary scores of the NKDKTS symptom checklist. As noted previously, the factor weights for each item were positive and ranged from 0.50 to 0.77. Because differences in these weights were so small, the correlation between the scale score based on weighted items versus unweighted items was r = 0.999. Therefore, we computed the total symptom score by summing the items, unweighted.

Subjects were categorized into four groups according to their haemoglobin scores: <10 g/dL; 10–12 g/dL; >12–13 g/dL and >13 g/dL. At baseline, 48 h and 7 days, subjects with lower haemoglobin values reported greater symptoms [baseline: F(1) = 5.87, P = 0.017; 48 h: F(1) = 8.38, P = 0.005; 7 days: F(1) = 7.60, P = 0.007; Table 6]. Univariate regression of symptoms onto haemoglobin at each time point yielded the following results:


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  		Table 6 NKDKTS symptom scores by haemoglobin category at baseline, 48 h and 7 days

 
  • baseline: r = 0.22, R2 = 0.05 (P = 0.028), intercept = 23.47, B = 1.13;
  • 48 h: r = 0.26, R2 = 0.07 (P = 0.01), intercept = 22.17, B = 1.30;
  • 7 days: r = 0.22, R2 = 0.05 (P = 0.028), intercept = 24.19, B = 1.15.

The cross-sectional relationship between haemoglobin and NKDKTS symptoms was stable over time. Haemoglobin accounted for 5–7% of the variance in symptom scores. On average, each additional 1 g/dL of haemoglobin was associated with a 1.1–1.3 increase in NKDKTS symptom score (indicating fewer symptoms).



   Discussion
Top
 Abstract
 Introduction
 Original development and...
 Materials and methods
 Results
 Discussion
Conclusion
 References
 
The objective of this study was to evaluate the psychometric properties of the NKDKTS symptom checklist as a measure of the frequency of anaemia-related symptoms. The survey was administered to 104 dialysis patients at baseline, 48 h and 7 days. The results provide evidence indicating that the RCT version of the NKDKTS symptom checklist is a valid and reliable measure of anaemia symptom frequency in the dialysis population.

The analysis showed that the NKDKTS symptom checklist had a stable single factor structure. An imposed 2-factor solution produced an unstable second factor and did not provide improvement over the single factor solution. The single factor had good and stable internal consistency, in which every item contributed positively to consistency, and the removal of any individual item decreased consistency. The factor had acceptable test–retest reliability. Intraclass correlation coefficients for each item ranged from moderate to large, and all were statistically significantly greater than zero. The results of the construct validity indicated that patients with lower haemoglobin scores reported more symptoms.

There are limitations to these data. First, the change in haemoglobin over the course of the week was small and did not allow for the testing of responsiveness. Future studies should be conducted in patients whose haemoglobin is more variable, e.g. those just beginning treatment with ESAs, or those experiencing and/or recovering from intercurrent events known to be associated with haemoglobin variability. The wider distribution of haemoglobin change scores would also allow for the determination of a clinically meaningful difference for this scale. Second, though the NKDKTS symptom checklist distinguished between patients at various haemoglobin levels, it best distinguished patients in the lowest range (<10 g/dL) from the other ranges evaluated (10 g/dL and above). It is worth noting that the mean scores at each haemoglobin level were stable over time, suggesting reliability in their ability to distinguish between patients within these ranges. Finally, scale validation is an iterative process. This investigation demonstrated construct validity, using a laboratory measure of anaemia, i.e. haemoglobin. Future validation studies should examine associations between NKDKTS symptoms and objectively and subjectively measured physical function; measures of health care use, though most especially transfusion; and other patient- and physician-assessed measures of quality of life.



   Conclusion
Top
 Abstract
 Introduction
 Original development and...
 Materials and methods
 Results
 Discussion
 Conclusion
References
 
The primary goal of this study was to present findings on the psychometric properties of the NKDKTS symptom checklist as a measure of anaemia symptoms in a population of dialysis patients. The results show that the questionnaire is reliable and valid. Since the psychometric properties of PROs should be based on accumulating evidence, we encourage others to confirm and expand on our findings in future research.

Conflict of interest statement. Dr Spiegel's work was supported by a grant from Amgen, Inc. M.G. and T.M. are employees of Amgen, Inc. The results presented in this paper have not been published previously in whole or part, except in abstract format.



   References
Top
 Abstract
 Introduction
 Original development and...
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 

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Received for publication: 19. 5.08
Accepted in revised form: 25. 8.08


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