Qual Life Res DOI 10.1007/s11136-015-1037-0

Development and validation of the Diabetic Peripheral Neuropathic Pain Impact (DPNPI) measure, a patient-reported outcome measure Meryl Brod1 • Steven I. Blum2 • Donald M. Bushnell3 • Abhilasha Ramasamy4

Accepted: 30 May 2015 Ó Springer International Publishing Switzerland 2015

Abstract Purpose Diabetic peripheral neuropathy (DPN) occurs in 26–47 % of diabetes patients and may have negative impacts on physical functioning, sleep, well-being, and quality of life. The Diabetic Peripheral Neuropathic Pain Impact measure (DPNPI) was developed to measure disease impacts and treatment effects. Presented are the DPNPI conceptual development and validation findings. Methods The DPNPI was developed following the FDA Guidance for Industry on patient-reported outcome (PRO) measures. Concept elicitation (CE) included literature review, clinical expert interviews, and patient interviews/focus groups. Qualitative data were analyzed following grounded theory principles, and draft items were cognitively debriefed. The measure underwent psychometric validation, and an a priori statistical analysis plan assessed the measurement model, reliability, and validity. Simultaneous analyses of item functioning were conducted using Rasch measurement theory (RMT). All tests were performed for the total score and each domain. Results Twenty-five patients and three clinical experts participated in CE which resulted in a 27-item validation ready measure. In the validation study (N = 124), nine & Meryl Brod [email protected] 1

The Brod Group, 219 Julia Avenue, Mill Valley, CA 94941, USA

2

GlaxoSmithKline, 2301 Renaissance Blvd., King of Prussia, PA 19406, USA

3

Health Research Associates, Inc., 6505 216th Street SW, Suite 105, Mountlake Terrace, WA 98043, USA

4

Actavis, Inc., Harborside Financial Center, Plaza V, Jersey City, NJ 07311, USA

draft items were dropped due to high missing data and/or high correlations between items. Factor analysis revealed three domains: physical functioning/mobility, sleep, and daily activities. RMT confirmed adequate item fit and placement within domains. Internal consistency ranged from 0.91 to 0.96 and test–retest from 0.84 to 0.91. All prespecified hypotheses for convergent and discriminant validity were met. Conclusions CE and psychometric results provide evidence that the final, 18-item DPNPI is a reliable and valid PRO measure of disease impacts and treatment for DPNP. Further validation work should include responsiveness assessment. Keywords Diabetic peripheral neuropathic pain
Adult functioning and well-being
Patient-reported outcomes
Psychometrics

Introduction Diabetic peripheral neuropathy (DPN) is a common complication of diabetes occurring in 26–47 % of patients [1], and up to 50 % of patients with DPN may experience pain [diabetic peripheral neuropathic pain (DPNP)] [2]. Studies have shown that patients with DPNP have poorer physical health as a result of nerve damage in toes, feet, or hands causing either loss of feeling or pain described as throbbing, stabbing, burning, or aching. Symptoms of DPNP can be continuous or intermittent [3, 4] with patients reporting increased pain at night when tired or stressed [5]. Some patients report that DPNP and/or numbness fluctuates throughout the day or night (n = 26; 37 %), while for others pain and/or numbness are constant (n = 22; 31 %) [6]. Additional physical consequences of DPNP include loss of

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balance and coordination, which impairs gait and increases the risk of falls, and an inability to feel injury [3, 4, 7, 8]. In addition to these physical impacts, several studies suggest that DPNP has negative impacts on quality of life physically (sleep, mobility, walking, energy, and vitality), overall perceptions of health, enjoyment of life, activities of daily life, employment, and recreational and social activities [1, 3, 5–7, 9–20]. Limited research suggests that these illness burdens may be experienced cross-culturally [21, 22]. Additionally, a recent study found over half of the respondents reported that DPNP symptoms impacted their work life negatively (n = 37; 53 %) [6]. Unfortunately, the majority of studies that evaluate these aspects of treatment have relied on non-DPNP-specific measures to assess outcomes [7, 9–11, 14], which may not fully capture how DPNP affects patients and, therefore, may not be sensitive to changes in patients’ functioning as a result of treatment. Given the multitude of negative health impacts that DPNP patients experience, it is imperative that patientreported outcome (PRO) measurement of these impacts and the effect of treatment be assessed with the most sensitive measures possible in order to assist clinicians, policy makers, payers, and patients in better understanding and tailoring treatment options. To address this gap, a disease-specific PRO, the Diabetic Peripheral Neuropathic Pain Impact (DPNPI) measure, was developed according to scientific principles outlined in the FDA Guidance for Industry: Patient-Reported Outcome Measures [23] and best practices [24, 25]. This paper presents the conceptual development and validation findings of the DPNPI.

Materials and methods

Data from clinical experts and patients were collected iteratively so that completed interviews were used to guide and inform subsequent interviews. The individual patient and expert clinician telephone interviews each lasted approximately 1 h, and in-person focus groups lasted approximately 2 h. The interview guides included openended questions regarding perceived impacts of DPNP on social, physical, and psychological aspects of life; productivity; treatment satisfaction; treatment compliance; and specific variables that act as moderators (i.e., factors that either increase or decrease the impact of DPNP). Results from the concept elicitation phase were then analyzed based on grounded theory principles of qualitative data analysis. Based on this analysis, a theoretical model of the impact of DPNP on adults was formulated. Concept elicitation sample Modeled after the clinical trial inclusion/exclusion criteria in which the DPNPI is likely to be included, eligible patients for interviews and focus groups were 18 and older; were able to read and speak English; were with at least a 12-month history of diabetes mellitus; and had a current daily pain rating of at least 4 on an 11-point (0–10) numerical rating scale (NRS). Exclusion criteria were body mass index [45 kg/m2, history of severe psychiatric disorder (e.g., psychotic disorder, history of suicide attempt/current suicidal ideation, current episode of major depressive disorder), presence of other forms of pain that could confound the assessment of DPNP, neuropathy due to other causes, any amputation or non-ambulatory (allowed ambulation with cane or walker), had active diabetic foot ulcers, or known severe peripheral artery disease of the extremities.

Conceptual phase Qualitative data analysis Concept elicitation process Concept elicitation data were gathered from three sources: review of DPNP literature, individual telephone interviews of international clinical experts, and qualitative data from patients with DPNP participating in either individual telephone interviews or focus groups. The literature search was conducted using the US National Library of Medicine’s PubMed database, with secondary searches in the search engine Google. Searching was limited to global, peer-reviewed journal articles published in English. The following keywords were relevant in the searches: diabetic peripheral neuropathy/neuropathic pain/painful diabetic neuropathy, quality of life, compliance, depression, coping, economics, sleep, or treatment satisfaction. The literature review was used to help develop questions for the clinician and patient semi-structured interview guides.

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All interviews and focus groups were audio-taped, transcribed, and coded using the qualitative analysis data software Atlas.ti version 6.2.28 [26]. Patient interview transcripts were analyzed and synthesized based on grounded theory principles. Grounded theory is a systematic method of qualitative data analysis that involves developing and refining theory based on concepts derived during the research process. When applying the grounded theory method, the researcher does not formulate hypotheses in advance, but rather they are identified as they emerge and are thus ‘‘grounded’’ in the data. Qualitative data are analyzed using a method of constant comparison, and data collection and analysis continue until saturation is identified (i.e., further data collection does not reveal new concepts) [27]. Transcripts were reviewed and coded at least three times. Additional review of transcripts occurred when a

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new code was added, to insure that all incidences of that theme were captured during the coding process. One individual coded all transcripts, thus eliminating problems associated with inter-coder reliability. Item generation Based on the conceptual model derived from the conceptual phase of the development process, items reflecting the domains were generated by identifying major themes and then using the language of the patient, as closely as possible, to reflect the content of the major themes of each domain. Once generated, items were cross checked with transcripts to confirm that there were sufficient patient quotes to support the content of the item. Cognitive debriefing The first version of the DPNPI was cognitively debriefed, using the think aloud method and according to an a priori item definition table. Respondents met the same eligibility criteria as the concept elicitation interviews. Participants were mailed or e-mailed the DPNPI in advance and asked to complete the instrument prior to a prearranged individual telephone interview to assess comprehension, wording, formatting, clarity, and relevance of items using verbal probing techniques. Cognitive debriefing was conducted in blocks of three patients each. After the first three participants were interviewed, findings were reviewed and a decision was made regarding whether any changes to the measure were necessary. This process continued in blocks of three participants until a determination was made that readability and relevance were acceptable based on consensus agreements between respondents in an entire block. Revisions to the measure were made according to the debriefing findings to produce a validation ready version of the measure. A second cognitive debriefing of the electronic version of the DPNPI was conducted to test the usability of the measure, contribute to the evaluation of the measure’s content validity, and to confirm that an electronic application of the DPNPI did not change the way respondents understood and interpreted items. Cognitive debriefing of the electronic measure was conducted in an independent sample of DPNP patients who met the same eligibility criteria as those participating in the first debriefing. Validation phase Procedures The validation study was a clinic-based, non-interventional study in which participants were asked to complete a 45-min paper and pencil validation battery survey. Patients

with DPNP were recruited by US physicians from their current case load or identified by chart review. To be eligible for the validation study, patients had to have been diagnosed with painful polyneuropathy for at least 6 months due to type 1 or 2 diabetes mellitus, to be over the age of 18, to be able to read English, to have been diagnosed with DPNP of any etiology, and were enrolled in one of the three cohorts depending on their current treatment regimen: (1) currently receiving treatment for DPNP for at least 1 month (maintenance group), (2) newly initiating DPNP therapy (new treatment group), and (3) not currently on prescription medication for DPNP for at least the past 6 months (no treatment group). Subjects attended a clinic visit where they received the validation battery and instructions to complete the survey including self-sealing it after completion in a stamped, preaddressed envelope. The validation battery included a demographic form and all measures needed to conduct the psychometric analyses to assess validity (convergent and known-groups) of the DPNPI. Participants in the new treatment group returned to the clinic for an 8-week followup visit that included a clinical examination to evaluate response to treatment and to complete an abbreviated qualitative assessment including the DPNPI. Participants in the no treatment and maintenance groups were asked whether they were willing to be retested and complete an additional 5-min DPNPI mail-in survey 2 weeks later in order to assess the test–retest reliability of the instrument. Participants with any changes to treatment or major life changes since their last assessment were excluded from the retest sample. The primary objectives of the DPNPI validation study were: to examine the item characteristics; perform item reduction; examine measurement model (scaling, factor structure); assess reliability and validity of the total score and each domain (known-groups validity, convergent validity test–retest reliability, internal consistency reliability); derive scoring methods (domain and/or total scores); and assess response burden. Validation battery measures In order to assess the psychometric properties of the total score and each domain of the measure, the following measures were administered at baseline along with the validation ready version of the DPNPI: Activity Impairment Assessment (AIA) [28], Sheehan Disability Scale (SDS) [29], Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) (Short Form) [30], SF-36v2 [31], Medical Outcomes Study Sleep scale (MOS-Sleep) [32], Fatigue Symptom Inventory (FSI) [33], patient-reported physical activity—2 item patient rating of how active they are during the day and how much DPNP interferes with their activity—and a brief demographic survey.

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Psychometric testing statistics

Validity testing

Item reduction and measurement model

To assess convergent construct validity, Pearson’s correlation was computed to measure the association between the total and/or subscale scores on the DPNPI measure and the other PROs included in the study. Specifically, we tested a priori hypotheses for each domain using a twotailed test at a p \ 0.05 levels. The guideline for acceptable magnitude of correlation was above 0.40. Discriminant (known-groups) validity evaluated the ability of the DPNPI to discriminate; a list of knowngroups and the direction in which the DPNPI should distinguish these groups was generated. The scores of the groups on the DPNPI domains were compared using oneway ANOVA with groups as a fixed factor. Effect size statistics (difference in means divided by the pooled standard deviation) were also reported. For domains with two hypotheses, at least one of the tested hypotheses must have been met to claim known-groups validity for that hypothesis.

Item reduction was performed based on a priori criteria to assess acceptable values for missing data, ceiling and floor effects, item-to-total and item-to-item correlations, and importance of conceptual relevance. An exploratory factor analysis using principal factor analysis or principal axis factoring with oblique rotation was examined expecting to derive unbiased estimates for the relationships between the latent constructs and subscales. The most appropriate number of factors to be extracted was determined using primarily residual analysis, i.e., evaluation of the ability of the factor solution to represent the correlation structure, using 0.40 as the minimum factor loading to be eligible as an item for a given factor, and clinical and theoretical interpretability of the solution. The expectation was that for items not loading to a factor, the factor loading would be \0.40. A scree plot of the principal component solution was used as guidance to the number of components with eigenvalues of [1.

Results Reliability testing Conceptual phase Cronbach’s alpha was used to assess internal consistency and test–retest reliability. A minimum correlation of 0.70 was expected to claim the instrument is internally consistent and has acceptable test–retest reliability. Rasch measurement theory (RMT) analysis A Rasch measurement theory (RMT) analysis was performed [34] to examine item fit and unidimensionality of the domains. The RMT model evaluation included overall fit statistics (infit and outfit) examining the intended construct of each domain. The data exhibit a good fit to the model if the expected values of the fit mean square (MNSQ) range between 0.8 and 1.2, and the standardized mean square (ZStd) ranges between -2.0 and 2.0. Item placement relative to other items was evaluated using the item separation index and item reliability. Good internal consistency should have a Rasch item reliability of 0.90 or higher. Category probability curves (item characteristic curves) were examined to identify items not demonstrating monotonically increased responses. A person-item distribution map was used to examine the distribution of the persons and items displayed together on a logit scale with the most able persons and most difficult items on one side and the least able persons and the easiest items on the other. Distances between items of 0.30 [35] logits or more were examined to avoid large gaps in the measurement. Response options having fewer than ten responses were considered underused.

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Concept elicitation A total of three clinical experts were interviewed. All were well-established endocrinologists, in practice 25 years or more, and seeing a minimum of 40 patients a year with DPNP. Twenty-five patients with DPNP participated in the focus groups and one-on-one interviews. In order to ensure a geographically representative sample, four focus groups (N = 23) were conducted in Los Angeles (n = 8), New York (n = 6), Chicago (n = 4), and Dallas (n = 5); two telephone interview participants were recruited from New York. The telephone interviews (N = 2) lasted approximately 1 h, and the focus groups lasted approximately 2 h. All interviews were conducted by an experienced qualitative researcher. Saturation of key concepts was reached after the third focus group, whereby no new, significant information was discussed in subsequent interviews. The conceptual phase patient focus group and individual interview sample (Table 1) was 68 % male, 60 % White, and 28 % Black, and the average age was 52 years. About half reported their marital status as married/partnered (52 %), working full time (64 %), and with an annual household income over $60,000 (48 %). The majority had type 2 diabetes (80 %), were obese or overweight (56 and 20 %, respectively), and over half (56 %) reported their diabetes as well controlled. The average duration with

Qual Life Res Table 1 Summary of qualitative sample description Demographics

Concept elicitation focus group and patient interviews (n = 25)

Cognitive debriefing interviews (n = 27)

Total qualitative sample (N = 52)

Female

8 (32)

12 (44)

20 (38)

Male

17 (68)

15 (56)

32 (62)

Married/partnered

13 (52)

10 (37)

23 (44)

Divorced

6 (24)

6 (22)

12 (23)

Single Widowed

4 (16) 2 (8)

7 (26) 4 (15)

11 (21) 6 (12)

White/Caucasian

15 (60)

19 (70)

34 (65)

Black/African

7 (28)

7 (26)

14 (27)

Latino/Hispanic/Mexican– American

2 (8)

0 (0)

2 (4)

Asian/Oriental/Pacific Islander

1 (4)

1 (4)

2 (4)

51.7 (26–70)

52.0 (32–70)

51.9 (26–70)

Gender # (%)

Marital status # (%)

Ethnicity # (%)

Age; mean (range) Work status # (%) Work full time for pay

16 (64)

12 (44)

28 (54)

Not working

6 (24)

10 (37)

16 (31)

3 (12)

5 (19)

8 (15)

Work part time for pay Income # (%) Over $60,000

12 (48)

14 (52)

26 (50)

Between $40,000 - $60,000

6 (24)

5 (19)

11 (21)

Between $20,000 - $40,000

4 (16)

5 (19)

9 (17)

Under $20,000

2 (8)

3 (11)

5 (10)

Not reported

1 (4)

0 (0)

1 (2)

Number of years have DPNP; mean (range)

5.1 (1–20)

5.1 (0.5–20)

5.1 (0.5–20)

Currently taking medication for DPNP # (%) Yes

17 (68)

19 (70)

36 (69)

No

8 (32)

8 (30)

16 (31)

5 (20)

6 (22)

11 (21)

20 (80)

21 (78)

41 (79)

Type of diabetes # (%) Type 1 Type 2

How well diabetes controlled # (%) Very well controlled

2 (8)

1 (4)

3 (6)

Well controlled

12 (48)

11 (41)

23 (44)

Moderately controlled

10 (40)

12 (44)

22 (42)

Poorly controlled

1 (4)

3 (11)

4 (8)

Very poorly controlled

0 (0)

0 (0)

0 (0)

6.9 (4–10)

–

–

18.5–24.9 (Normal)

4 (16)

–

–

25–29.9 (Overweight) 30.0 and above (Obese)

5 (20) 14 (56)

– –

– –

Not reported

2 (8)

–

–

Pain ratinga, b; mean (range); n = 23 BMI # (%)a; n = 23

a

Data collected only for concept elicitation focus group and patient interviews

b

Pain was rated on an 11-point scale with 0 being ‘‘no pain’’ and 10 being the ‘‘worst pain I can imagine’’ in the past week

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DPNP was 5 years (range 1–20); patients had an average self-reported pain rating of 6.9 (range 4–10); and over twothirds were currently taking medication for DPNP (68 %). The analysis, based on ground theory, used a multistep process of examining individual statements and then summarizing, grouping and coding into categories, and examining moderating variables. The results of the analysis were then reviewed by the study team in an in-person meeting to confirm that codes were conceptually appropriate and that grouping of statements into categories (areas of impact) was consistent with the concepts. The analysis identified four major areas of impact: (1) physical function: walking, exercise, energy, standing, balance, bending, and mobility; (2) daily life: productivity, recreational activities, work, enjoyment, focus, and chores; (3) social/psychological: anxiety, friends/family, irritability, depression, and fear; and (4) sleep: sleep, falling asleep, waking in the night, returning to sleep, and not feeling rested upon awakening. These impacts were collapsed into two overarching functioning domains: physical functioning (including Sleep and Mobility) and daily functioning (including daily activities and relationships). Item generation The project team then generated items for each area of impact that reflected the content of the statements that were grouped to that concept. Items were generated using, as closely as possible, words expressed by patients in the interviews to reflect the concept being captured by that item. This process resulted in the generation of a 27-item preliminary version of the DPNPI measure. All items on the DPNPI had a five-point categorical response scale ranging from ‘‘Never/Almost Never’’ to ‘‘Almost Always/ Always.’’ The recall period for the DPNPI is 1 week. Cognitive debriefing A total of 27 subjects participated in the cognitive debriefings. For the paper version (N = 9), three blocks of three participants each were necessary to refine the items in terms of readability and relevance and produce the validation ready DPNPI. For the electron version (N = 18), six blocks of patients were interviewed before consensus between an entire block was reached. The sample for the cognitive debriefing (Table 1) was predominately male (56 %) and married/partnered (37 %) with an average age of 52 years (range 32–70); the majority of participants were White (70 %). About half were working full time (44 %) and had an annual household income over $60,000 (52 %). Over three-quarters had type 2 diabetes (78 %) and reported their diabetes as well to moderately controlled (85 %). The average duration

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with DPNP was 5.1 years (range 0.5–20), and over twothirds were currently taking DPNP medication (70 %). Content validity Feedback from the US Food and Drug Administration, (FDA) Center for Drug Evaluation and Research, Office of New Drugs review of the qualitative research dossier confirmed that the study sample was appropriate, that saturation was reached, and that the validation ready version of the DPNPI had achieved content validity. FDA did provide feedback that the social impact items were viewed as too distal and recommended removing such items from the instrument scoring if the measure was intended to support a labeling claim. Validation phase Sample characteristics One hundred twenty-four patients (N = 124) were recruited (maintenance and new treatment groups (n = 67) and no treatment group (n = 57). A subset of 105 patients from the no treatment and maintenance groups voluntarily completed the DPNPI a second time, approximately 2 weeks later, to assess reproducibility. The demographic characteristics of the study population appear in Table 2. Item reduction Nine items were dropped from the preliminary 27-item measure during item reduction resulting in an 18-item final version of the DPNPI. Items were dropped for response distributions showing high missing data and high correlations between items that were conceptually similar or for conceptual reasons (e.g., being considered a distal rather than proximal impact). There were no issues regarding either the ceiling effect or item-to-total correlations for the final 18 items. Measurement model After item reduction was completed, the exploratory factor analysis was performed and it was determined that the DPNPI has three distinct domains which were labeled ‘‘physical/mobility,’’ ‘‘sleep,’’ and ‘‘daily activities.’’ This model explained 74.7 % of total variance. Table 3 shows the factor analysis for the final DPNPI. Item-to-domain correlations were significant ranging from 0.721 to 0.925. Further, to provide justification for an overall total score, each factor was included in a second-order factor analysis.

Qual Life Res Table 2 Summary of validation sample description—demographics and DPNP history Demographic characteristics

Gender

Marital status

Living arrangement

Race

Age (Years)

Work status

Education

Combined yearly household income

How long have had DPNP (Years)

How old when you were diagnosed with DPNP (Years)

New treatment N = 6 (100 %)

Maintenance N = 61 (100 %)

No treatment N = 57 (100 %)

Total N = 124 (100 %)

N (%) Male

2 (33)

33 (54)

34 (60)

69 (56)

N (%) Female

4 (67)

27 (44)

23 (40)

54 (43)

N (%) Missing N (%) Single

– –

1 (2) 5 (8)

– 10 (18)

1 (1) 15 (12)

N (%) Married

2 (33)

33 (54)

31 (54)

66 (53)

N (%) Partnered

2 (33)

1 (2)

1 (2)

4 (3)

N (%) Divorced

1 (17)

16 (26)

9 (16)

26 (21)

N (%) Widowed

1 (17)

6 (10)

6 (11)

13 (10)

N (%) Alone

2 (33)

15 (25)

17 (30)

34 (27)

N (%) With others

4 (67)

38 (62)

35 (61)

77 (62)

N (%) Missing

–

8 (13)

5 (9)

13 (10)

N (%) White/Caucasian

4 (67)

48 (79)

33 (58)

85 (69)

N (%) Black/AfricanAmerican

1 (17)

7 (11)

9 (16)

17 (14)

N (%) Latino/Hispanic/ Mexican–American

1 (17)

6 (10)

11 (19)

18 (15)

N (%) Group not listed

–

–

2 (4)

2 (2)

N (%) Missing

–

–

2 (4)

2 (2)

Mean (SD)

65 (13)

62 (10)

62 (11)

62.8 (11.1)

Median

69

63

66

64.5

Range

46–79

35–78

34–80

34–80

N (%) Work full time for pay

2 (33)

7 (11)

12 (21)

21 (17)

N (%) Work part time for pay

–

4 (7)

10 (18)

14 (11)

N (%) Not working

4 (67)

50 (82)

33 (58)

87 (70)

N (%) Student

–

–

2 (4)

2 (2)

N (%) Grade School or Less

2 (33)

5 (8)

5 (9)

12 (10)

N (%) High School or Technical School

2 (33)

31 (51)

25 (44)

58 (47)

N (%) College

1 (17)

9 (15)

18 (32)

28 (23)

N (%) Graduate or Professional School

1 (17)

16 (26)

9 (16)

26 (21)

N (%) Under $20,000

1 (17)

24 (39)

20 (35)

45 (36)

N (%) Between $20,000 and $40,000

5 (83)

17 (28)

20 (35)

42 (34)

N (%) Between $40,000 and $60,000

–

5 (8)

3 (5)

8 (6)

N (%) Over $60,000

–

13 (21)

14 (25)

27 (22)

N (%) Missing

–

2 (3)

–

2 (%)

Mean (SD)

4 (3.2)

8.8 (7.9)

6.9 (5.8)

7.7 (7)

Median

3

6

5

5

Range

1–10

1–35

1–25

1–35

Mean (SD)

60 (14)

52.2 (15.8)

51.8 (19.3)

52.4 (17.4)

Median

65.5

54.0

57.0

55.0

Range

36–74

1–78

1–75

1–78

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Qual Life Res Table 2 continued Demographic characteristics

New treatment N = 6 (100 %)

Maintenance N = 61 (100 %)

No treatment N = 57 (100 %)

Total N = 124 (100 %)

5.5 (1.6)

5.7 (2.0)

5.2 (1.8)

5.5 (1.9) 60 (48.4)

Pain ratinga

Mean (SD)

Are you taking any medication for your DPNP?

N (%) No

1 (17)

5 (8)

54 (95)

N (%) Yes

5 (83)

56 (92)

3 (5)

64 (51.6)

Diabetes type

N (%) type 1 diabetes

1 (17)

3 (5)

3 (5)

7 (5.6)

N (%) type 2 diabetes

3 (50)

44 (72)

40 (70)

87 (70.2)

N (%) Missing

2 (33)

14 (23)

14 (25)

30 (24.2)

N (%) Very well controlled

1 (17)

10 (16)

10 (18)

21 (16.9)

N (%) Well controlled

4 (67)

20 (33)

18 (32)

42 (33.8)

N (%) Moderately controlled

1 (17)

24 (39)

25 (44)

50 (40.3)

N (%) Poorly controlled

–

5 (8)

3 (5)

8 (6.5)

N (%) Very poorly controlled

–

1 (2)

–

1 (0.8 )

N (%) Missing

–

1 (2)

1 (2)

2 (1.6)

N (%) Excellent

1 (17)

–

3 (5)

4 (3.2)

N (%) Very good

2 (33)

12 (20)

16 (28)

30 (24.1)

How well controlled your diabetes is?

Health in general

a

N (%) Good

2 (33)

23 (38)

21 (37)

46 (37.0 )

N (%) Fair

1 (17)

18 (30)

15 (26)

34 (27.4)

N (%) Poor

–

6 (10)

1 (2)

7 (5.6)

N (%) Missing

–

2 (3)

1 (2)

3 (2.4)

Pain was rated on an 11-point scale with 0 being ‘‘no pain’’ and 10 being the ‘‘worst pain I can imagine’’ in the past week

The results found that a single component with coefficients ranging from 0.794 to 0.885 existed. The total variance explained was 74.7 %. Rasch measurement theory analysis The fit statistics were within range for the items that were retained in the final DPNPI, and the person-item distribution (Fig. 1) suggests that the items included in the final version of the DPNPI appropriately target the core constructs that affect people with peripheral neuropathy. Reliability testing Internal consistency coefficients of the DPNPI (total score and all domains) are high, ranging between 0.91 and 0.96 (Table 4). The results showed that the instrument is internally consistent, suggesting that the scale or subscale is measuring a single construct. The test–retest coefficients of the DPNPI (total score and all domains) are also acceptable, ranging from 0.84 to 0.91, indicating reliability and stability of the instrument over time.

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Validity testing Convergent The results confirmed convergent validity of the measure as proposed in the hypotheses. As seen in Table 5, the association between the total and/or subscale scores on the DPNPI measure and the other logically related measures included in the study showed strong significant correlations between the measures. Known-groups validity All known-groups hypotheses were confirmed, and the DPNPI was able to discriminate between expected known relationships. Results showed that the DPNPI total score is significantly associated with severity of illness of PGI (1. marked to extremely severe, 2. moderately severe, 3. mildly to not at all severe; F = 30.624, p \ 0.001; effect size 1.35) and CGI (1. marked to extremely severe, 2. moderately severe, 3. mildly to not at all severe; F = 9.201, p \ 0.001; effect size 0.98). The direction of the relationship indicated that the DPNPI total scores decreased as disease severity decreased. The DPNPI physical/mobility score decreased as pain interference decreased (1. pain does not interfere at all, 2. pain interferes a little/somewhat, 3. pain interferes a

Qual Life Res Table 3 Factor analysis of the DPNPI Rotated component matrixa

Component 1

2

3

Physical/mobility Q05.DPNPI.06—Bending, stooping, and/or squatting

0.796

Q02.DPNPI.03—Going up and/or down stairs

0.784

Q06.DPNPI.07—Standing for short periods of time

0.773

Q03.DPNPI.04—Physically getting out of bed

0.766

Q07.DPNPI.08—Standing for long periods of time

0.760

Q04.DPNPI.05—Your balance (feeling steady on your feet) Q01.DPNPI.01—Walking

0.731 0.719

Q08.DPNPI.09—Sitting for long periods of time

0.690

Q14.DPNPI.18—Household chores (for example, shopping, cooking, cleaning)

0.669

0.571

vQ15.DPNPI.19—Personal care (for example, showering, bathing, dressing)

0.561

0.475

Sleep Q10.DPNPI.11—Staying asleep through the night

0.885

Q11.DPNPI.12—Getting back to sleep when you wake up during the night

0.862

Q12.DPNPI.14—Having a good night’s sleep

0.833

Q09.DPNPI.10—Falling asleep Q13.DPNPI.16—Need to take a nap and/or rest to catch up on sleep

0.823 0.415

0.504

0.484

Daily activities Q17.DPNPI.21—Your ability to complete tasks and/or activities in a timely manner

0.434

0.817

0.517

0.664

Q16.DPNPI.20—Your ability to concentrate and/or focus on what you are doing Q18.DPNPI.22—Your ability to do tasks and/or activities independently (for example, driving and/or cleaning without help from others) a

0.794

Rotation converged in five iterations

b

Extraction method: principal component analysis; rotation method: promax with normalization

c

Coefficients are not included if lower than 0.40

d

Items with items which loaded in more than 1 domain were assigned to a domain based on both conceptual relevance and the strength of the correlation

Fig. 1 Person-item map. aIndividual item logits were not fixed

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Qual Life Res Table 4 ICC statistics of the DPNPI

Scale identification

Alpha coefficients* (n = 124)

Test retest reliability** (n = 105)

Physical/mobility (8 items)

0.938

0.835

Sleep (5 items)

0.920

0.859

Daily activities (5 items)

0.909

0.896

DPNPI total (18 items)

0.959

0.914

* Reliability based on internal consistency using Cronbach’s alpha, using all patient samples (N = 124) ** Test–retest reliability was calculated using a subset (n = 105) of the sample who returned the retest measure. The retest period was 2 weeks Table 5 Convergent validity of the DPNPI: correlation matrix (N = 124)a SDSb

SF-36 Physical functioning

MOS-Sleepb disturbance

AIAb

Physical/mobility

0.649**

-0.470**

0.259**

0.724**

–0.579**

Sleep

0.603**

-0.391**

0.453**

0.590**

-0.425**

Daily activities

0.731**

-0.439**

0.322**

0.787**

-0.565**

DPNPI total

0.741**

-0.493**

0.375**

0.792**

-0.607**

SF-36 Social functioning

** Correlation is significant at the 0.01 level (two-tailed) a

Convergent validity hypotheses were

H01: Total score: DPNPI total will be related to overall disability (SDS total score) H02: Physical function/mobility subscale: DPNPI—mobility will be related to physical function of the SF-36 (SF-36 physical/mobility scores) H03: Physical function/sleep subscale: DPNPI—sleep will be related to impact on sleep/sleep quality (MOS-Sleep scores) H04: Daily functioning/daily activities subscale: DPNPI—daily activities will be related to impact on performing daily activities (AIA scores) H05: Daily functioning/social relationship subscale: DPNPI—social relationship will be related to impact on social relationship of SF-36 (SF-36 social subscale) b

SDS Sheehan disability scale, MOS-Sleep medical outcomes sleep disturbance subscale, AIA activity impairment assessment

lot/a great deal; F = 58.405, p \ 0.001; effect size 2.08). The DPNPI sleep subscale was significantly associated with FSI (tertiles; F = 23.218, p \ 0.001; effect size 1.27) in positive direction; the DPNPI sleep score increased as degree to which fatigue is interfering with daily life increased. Finally, the DPNPI daily activities subscale was also significantly associated with Q-LES-Q SF score (tertiles; F = 34.483, p \ 0.001; effect size 1.46); the DPNPI daily activities score decreased as degree of satisfaction and enjoyment of life increased. Administration and scoring The DPNPI takes approximately 10 min to complete. The scale items are aggregated into scales using a standard algorithm which does not standardize nor weight the items. DPNPI items and domains are scored so that a lower score indicates a better health state. The measure can be scored as three independent domains or as a total score. Theoretical framework Based on the findings from both the conceptual and the validation phases, a revised theoretical framework of the impact of DPNPI on functioning was developed (Fig. 2).

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Validated DPNPI The final validated measure contains 18 items, in 3 domains, as shown in the conceptual model in Fig. 3.

Discussion Disease-specific PROs which measure small as well as larger changes in patient functioning and well-being are crucial for assessing treatment benefit, tailoring treatment decisions to individuals, and providing data to make informed regulatory and payer decisions. The DPNPI, as a disease-specific measure, developed according to rigorous scientific principles [36–38], and found to have adequate validity and reliability, should provide a more targeted and responsive assessment of the impact of DPNP than generic measures. Further, since each domain of the DPNPI has been validated as well as the total score, the specific impacts of DPNP physical/mobility, sleep, and daily activities can be independently assessed. These domains were hypothesized based on findings from the concept elicitation phase and confirmed in the factor analysis. The total score is meant as an overall rating of the impact of DPNP for these domains.

Qual Life Res Fig. 2 Theoretical model

Fig. 3 Conceptual model

The concept elicitation done to support the DPNPI strongly supports that there is substantial burden for patients with DPNP and that functioning, both in terms of physical and daily activities, is negatively impacted. It should be noted that patients also reported experiencing negative psychological and social impacts; however, items related to these concepts were removed for conceptual reasons based on feedback from FDA. However, given that the measure was intended to assess the impact of disease on functioning, the DPNPI does not capture these more distal psychological and social impacts. Further, there are important modifiers which can either lessen or increase the impact of disease, which should be taken into consideration when assessing the impact of living with DPNP. Although

some of these modifiers, such as timing of pain, are not amenable to intervention, there are other modifiers, such as social support, which may be important to consider when developing treatment plans. The findings from the validation study suggest that the DPNPI is psychometrically sound. The measurement model explained a major portion of the total variance (74.7 %), correlations indicate a strong relationship between items and internal consistency with its respective domain, and the fit statistics suggest that the final version of the DPNPI does address the core constructs that affect those with DPNP. Additionally, all hypothesized relationships for both convergent and known-groups validity were supported. However, validation is an iterative process, and

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Qual Life Res

as such, the DPNPI should be validated further with a larger sample size and ideally in a clinical trial setting. Further, this study did not enroll enough new treatment group subjects in order to examine responsiveness or the minimally important clinical difference for the measure. Ideally, these should be assessed in an interventional study. This study used a factor analysis approach to assess the underlying structure of the DPNPI with the assumption that diabetic peripheral neuropathy has an effect on each item within each domain. Factor analyses have been used for many years to evaluate/confirm factor structures for patientreported outcome measures [38–41] and are considered best practice for analyzing and confirming such hypothesized factor structures. In this study, we took into consideration that respondents could potentially suffer from symptoms that may not be related to DPNP; therefore, to help guide and interpret the factor structure, all items of the DPNPI ask specifically about how DPNP interferes with aspects of peoples’ lives. We recognize that although the methodology used may consider the patient’s perceptions of their condition’s impact on and interference with daily functioning as latent variables, the personal underlying judgment may be imperfectly measured even if the list of symptoms and impairments on the scale is not latent in and of itself. However, the scope of this instrument development is for use in clinical trials and drug development, where such exploratory and confirmatory factor analyses have been traditionally used. We recognize that there are other, more recent factor analysis approaches one could employ, for instance network analyses [42, 43], which offer a different conceptualization in terms of a network approach where disorders are conceptualized as systems of causally connected symptoms rather than as effects of a latent disorder. Such modern techniques and analyses were not within the scope of the current study, but could be explored in future studies where they may provide additional insights into the relationship between the symptoms and impacts associated with diabetic peripheral neuropathy. As with all studies, limitations of this study should be acknowledged. First, this study was conducted in a US English-speaking population. The recognition and reporting of pain have been shown to be culturally influenced [44, 45], and further study of the use of the DPNPI in other cultures is warranted. Additionally, even though the characteristics of this study appear to be representative of the characteristics of the larger DPNP population, certain exclusion criteria were imposed due to the need to match this sample to expected upcoming clinical trial samples. Thus, the generalizability to findings to the broader DPNP population who may not meet the strict eligibility criteria for clinical trials is unknown. Further use of the DPNPI in general clinical practice would be very helpful in understanding some of these potential biases.

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In summary, the conceptual elicitation and psychometric results provide evidence that the final, 18-item DPNPI is a reliable and valid PRO of the impact of disease and treatment on patient functioning. Further research is required to demonstrate responsiveness and to determine score changes which are considered clinically meaningful. Accurate assessment of the impact of DPNP on patient functioning will help clinicians to develop more targeted treatment plans as well as facilitate discussion with their patients on what are realistic expectations for living with DPNP. For researchers as well as clinicians, accurately capturing these impacts will help to assess both the efficacy and the effectiveness of interventions and treatments. This may help facilitate the development of improved treatments and assess the benefit of current treatments. Acknowledgments This study was funded by Forest Research Institute Inc. a subsidiary of Actavis plc. We would like to acknowledge and thank Juliana Setyawan and Robyn Carson for their contributions during the qualitative development stage of the project. Conflict of interest Dr. Brod and Mr. Bushnell are paid advisors/consultants to Forest Research Institute. Ms. Ramasamy is an employee of Actavis, Inc., and Mr. Blum is a former employee of Forest Research Institute, who is now employed by GlaxoSmithKline. Ethical standard All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Institutional Review Board approval was granted by Copernicus Group IRB: #TBG1-11-483. Informed consent Informed consent was obtained from all individual participants included in the study.

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