Journal of the Peripheral Nervous System 19:104–114 (2014)
RESEARCH REPORT
Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy Etta J. Vinik1 , Aaron I. Vinik1 , James F. Paulson2 , Ingemar S. J. Merkies3,4 , Jeff Packman5 , Donna R. Grogan5 , and Teresa Coelho6 1 Eastern Virginia Medical School, Strelitz Diabetes Center, Norfolk, VA, USA; 2 Department of Psychology, Old Dominion University, Norfolk, VA, USA; 3 Department of Neurology, Spaarne Hospital, Hoofddorp, The Netherlands; 4 Department of Neurology, Maastricht University Medical Centre, Maastricht, The Netherlands; 5 FoldRx Pharmaceuticals, Inc., A Wholly-Owned Subsidiary of Pfizer Inc., Cambridge, MA, USA; and 6 Centre for the Study of Amyloidoses, Hospital Santo António, Porto, Portugal
Abstract The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire is an instrument to assess QOL in diabetic polyneuropathy. The objective of this observational, cross-sectional study in 61 patients with V30M transthyretin familial amyloid polyneuropathy (TTR-FAP) and 16 healthy volunteers was to validate the Norfolk QOL-DN for assessment of QOL in TTR-FAP. Comparisons were conducted to identify the best items to discriminate disease stages and assess which individual Norfolk domains (symptoms, large fiber, small fiber, autonomic, and activities of daily living) would be most affected by disease stage. Analysis of individual items revealed a significant pattern of discrimination among disease stages (p < 0.001). Total QOL scores increased (indicating worsening) with duration of symptoms, with a steeper increase observed earlier in the course of disease. Significant correlations were observed between each Norfolk domain and other measures of neurological function. Limitations include cross-sectional study design, low patient numbers in this rare disease, and the ordinal-based character of the metric used; future areas to explore include item response theory approaches such as Rasch analysis. These results suggest the Norfolk QOL-DN is a reliable indicator of the impact of disease severity on QOL in patients with TTR-FAP. Key words: nerve-fiber function, neurological function, Norfolk quality of life, outcome measure, transthyretin amyloid polyneuropathy
Introduction
fibrillar proteins (amyloid) accumulate in tissues in amounts sufficient to impair normal function. A number of different precursor proteins have been associated with familial amyloidosis, including transthyretin (TTR; formerly known as pre-albumin), gelsolin, and apolipoprotein. TTR is primarily synthesized in the liver and circulates in the blood as a transport protein of thyroxine and retinol-binding protein-retinol (vitamin A) complex (Blake et al., 1978; Monaco et al., 1995). In its native state, TTR exists as a homotetramer with two C2 symmetric funnel-shaped thyroxine-binding sites
Systemic amyloidoses encompass both acquired and inherited conditions in which various insoluble
Address correspondence to: Aaron Vinik, MD, PhD, FCP, MACP, FACE, Murray Waitzer Endowed Chair of Diabetes Research, Director of Neuroendocrine Unit, Eastern Virginia Medical School, Strelitz Diabetes Center, 855 W. Brambleton Avenue, Norfolk, VA 23510, USA. Tel: +(1)757-446-5912; Fax: +(1)757-446-5868; E-mail: [email protected]. © 2014 Peripheral Nerve Society
104
Vinik et al.
Journal of the Peripheral Nervous System 19:104–114 (2014)
available (Vickrey et al., 2000; Vileikyte, 2001; Vinik et al., 2005). One such instrument is the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire, which was developed to address the need for a tool to assess patients’ subjective perceptions of symptoms associated with specific nerve fiber damage occurring in DN (Vinik et al., 2005; Vinik and Vinik, 2007; Vinik et al., 2008). This self-administered questionnaire captures patients’ perceptions of a wide spectrum of neuropathy symptoms and is a nerve fiber-specific tool comprising five domains: physical functioning/large-fiber neuropathy, ADL, symptoms, small-fiber neuropathy, and autonomic neuropathy (Vinik and Vinik, 2007). Presence or absence of neuropathic symptoms is recorded, and items assessing ability to perform ADL, as well as generic health status, are rated on a 5-point Likert-type scale, with higher scores indicating poorer status. The Norfolk QOL-DN has been validated in populations with mild-to-severe DPN (Vinik and Vinik, 2007; Vinik and Ziegler, 2007; Vinik et al., 2008) and discriminates DPN patients from healthy controls, shows excellent reproducibility, and can discriminate across different levels of disease severity (Vinik et al., 2005; Vinik and Vinik, 2007; Vinik et al., 2008). The authors have shown previously (Vinik et al., 2005; 2008) that the primary influences on QOL in DPN are physical functioning and ADL, accounting for 59.7% of the variance. Effects on ADL appear to be primarily determined by fine motor functions, in contrast to the greater influence of gross motor requirements for activities in the physical functioning/large-fiber domain. The rapid loss of motor function in the TTR-FAP patient population, resulting in confinement to a wheelchair, clearly would be expected to affect both ADL and physical functioning, with a substantial impact on QOL. The main objective of this study was to assess the validity and reliability of the Norfolk QOL-DN as an index of health-related QOL in patients with the rare disease TTR-FAP. We have evaluated its ability to discriminate between the different levels of TTR-FAP disease severity at early and later stages of disease. We also examined the relationships, by TTR-FAP disease stage, between the Norfolk QOL-DN and objective measures of nerve-fiber function, autonomic function, and impairment due to neuropathy.
located at the central dimer–dimer interface (Nilsson et al., 1975; Saraiva, 2001). While TTR-familial amyloid polyneuropathy (TTR-FAP) is a rare disease with variable penetrance and onset in those carrying a causative mutation, it represents the most common form of familial amyloidosis and is an axonal degenerative disease affecting sensory, motor, and autonomic function that is fatal over an average time of 10 years from symptom onset (Benson, 1989; Planté-Bordeneuve and Said, 2011; Coelho et al., 2013). As this axonal degeneration begins in the distal small unmyelinated fibers involved with pain and temperature sensation, the initial symptoms are hypoesthesia, paresthesia, and loss of sensation in the lower limbs (LLs) (Thomas and King, 1974; Benson, 1989; Planté-Bordeneuve and Said, 2011), in a pattern similar to that observed in diabetic polyneuropathy (DPN) (Boulton et al., 2005; Vinik et al., 2013). As with DPN, progression of TTR-FAP is accompanied by greater involvement of the upper limbs and progression to more extensive motor involvement. The extent to which a patient’s walking ability is impaired is a particularly salient sign of disease progression. The Coutinho classification system for TTR-FAP disease progression utilizes three stages which are based on limb involvement; the disruption of activities of daily living (ADL); the severity of sensory, motor, and autonomic neuropathic dysfunction; and ambulation status (Coutinho et al., 1980). Autonomic neuropathy may be the presenting symptom or it may be seen somewhat later, usually within 1–2 years of disease onset. Symptoms such as nausea, vomiting, constipation alternating with diarrhea, urinary retention or incontinence, anhidrosis, orthostatic hypotension, and sexual impotence may be present (Coutinho et al., 1980). Health-related quality of life (QOL) can be measured by a variety of self-administered questions regarding perceived aspects of physical and mental health and function (McHorney, 1999; Centers for Disease Control and Prevention, 2000). Despite the substantial deleterious impact that TTR-FAP would be expected to have on health-related QOL, there have been very few reports of health-related QOL evaluations in this patient population. Of the studies that have addressed this important issue, most have sought to characterize QOL specifically in patients who have undergone liver transplantation. Nearly all these studies have utilized generic health-related QOL instruments, such as the Medical Outcome Study 36-item short-form survey, which have not been validated in TTR-FAP (Jonsén et al., 1996; Jonsén et al., 2001; Drent et al., 2009). The lack of a specific tool with which to evaluate QOL in TTR-FAP stands in contrast to DPN, for which several validated instruments are
Materials and Methods Study protocol and participants This was an observational, cross-sectional study conducted in 61 TTR-FAP patients with the Val30Met mutation and 16 healthy volunteers who were between 105
Vinik et al.
Journal of the Peripheral Nervous System 19:104–114 (2014)
LL (total score range, 0–88) and combines subscale scores for muscle weakness (range, 0–64), reflexes (range, 0–8), and sensation at the great toe (range, 0–16) (Dyck et al., 1997). The NIS-LL is particularly appropriate for the assessment of early-stage disease (Ziegler et al., 2011). To enhance reproducibility, the average of two successive NIS-LL assessments performed by the same neurologist at least 24 h apart (but within 7 days) was used in the analysis. Quantitative sensory testing was performed utilizing the Computer Aided Sensory Evaluator IV (WR Medical Electronics, Stillwater, MN, USA), a computerized test of sensory threshold determination. Cooling detection threshold (CDT), vibratory detection threshold (VDT), and heat/pain detection threshold (HPDT) of the upper and lower limbs (CDT and HPDT assessed at the dorsum of the foot and hand; VDT assessed at the dorsum of the great toe and index finger) were determined. The heart rate response to deep breathing (HRDB) was assessed only in those patients without pacemakers.
18 and 50 years of age without neurological disease. The TTR-FAP cohort comprised patients with stage 1 disease at baseline who were participants in a phase II/III interventional study (n = 29), in addition to stage 2 (n = 16) and stage 3 (n = 16) patients. All patients were enrolled at a single study center (Hospital Santo António, Porto, Portugal) and the study protocol was approved by the institutional review board. The Val30Met mutation is endemic in Portugal with 90% penetrance. Disease staging of TTR-FAP was based on the criteria established by Coutinho et al. ( 1980) and determined primarily by ambulatory status: stage 1, fully ambulatory; stage 2, required assistance with ambulation; and stage 3, wheelchair-bound.
Measures QOL was measured using the 35-item Norfolk QOL-DN questionnaire (Vinik et al., 2005; Boyd et al., 2011), developed to reflect symptoms associated with damage to various nerve fiber types (Vinik and Vinik, 2007; Vinik et al., 2008). Following interviews with >1,000 patients, specific items were selected to address the symptoms, complications, and impairment of ADL associated with small and large nerve fibers and autonomic nerves. The original 68-item pool was refined into a 47-item questionnaire, which was then evaluated for its discriminatory ability and found to have sensitivity >75% across all domains and specificity between 71% and 90% (Vinik et al., 2005; Vinik and Vinik, 2007). Following assessment of test/retest reliability and psychometric factor analysis, the Norfolk QOL-DN was further refined to 35 items (Vinik and Vinik, 2007). The questionnaire was translated into Portuguese under the direction of the first two authors using forward/backward translation and cognitive debriefing with FAP patients and linguistically validated (Mapi Research Institute, Lyon, France). Study participants completed the Norfolk QOL-DN questionnaire at baseline and 4 weeks later (except for the stage 1 patients, who were not assessed at week 4). List-wise deletion was used to handle missing data. The scoring approach used in this study yielded a possible range for total quality of life (TQOL) scores of −2 to 138. The validity of the Norfolk QOL-DN for assessing the TTR-FAP population was further delineated by correlating it with objective measures of neurological function, evaluated using a modified form of the neuropathy impairment score (NIS) (Dyck et al., 1995; Casellini et al., 2007), the NIS-Lower Limbs (NIS-LL) (Dyck et al., 1997; Bril, 1999), and quantitative sensory testing. The NIS quantifies a neurological examination (total score range, 0 [normal] to 244 [total impairment]), a tool commonly used to assess clinical efficacy in the treatment of neuropathy. The NIS-LL is restricted to the
Analytical methods Prior to the primary analyses of the differences between QOL in TTR-FAP disease stages, all items were screened for floor or ceiling effects, invariance, or other problems that might compromise their utility in further analysis or in practice. Thereafter, several analytical techniques were used. Due to the descriptive nature of these analyses and the small sample size inherent in this orphan disease population, no corrections were made for multiple comparisons.
Exploratory factor analysis As the Norfolk QOL-DN has 35 items scored in five domains, a forced five-factor extraction was used in the initial exploratory factor analysis for the QOL instrument in the TTR-FAP population. Varimax rotation was used to produce a more clearly interpretable factor structure. Exploratory factor analysis was used for the initial statistical approach because it allows identification of the common factors underlying the scale items. However, because the sample size was relatively small compared with standard psychometric studies, additional analyses were also conducted as described in the following sections. Test/retest reliability of the Norfolk QOL-DN in TTR-FAP The reliability of the Norfolk QOL-DN questionnaire has previously been tested in different DPN study populations, including diabetic controls free of evidence of neuropathy and patients with mild neuropathy, as well as healthy controls. The questionnaire was administered at study entry and again 4 weeks 106
Vinik et al.
Journal of the Peripheral Nervous System 19:104–114 (2014)
after the date of entry (Vinik et al., 2005), and was shown to have acceptable test/retest reliability in these populations. The same methodology was used to assess the test/retest reliability of both the Norfolk QOL-DN and its individual domains. Paired t-tests were used to compare the scores collected at study entry and week 4. Patients enrolled in the current interventional study were not retested.
neuropathy were determined for strength, reflexes, and somatosensory function, and the composite NIS-LL was derived as a sum of the scores of the individual components of the examination, as reported by Casellini et al. ( 2006). Objective scores have been shown to correlate with the individual domains of the QOL-DN in DPN and form the basis of criterion validity (Vinik et al., 2005; Vinik et al., 2008).
Measurement of disease progression over time, discriminatory validity, and item discrimination by disease stage Correlations between Norfolk QOL-DN domain scores and time from symptom onset were examined, with the hypothesis that there would be a significant association between disease progression and worsening scores on the Norfolk QOL-DN. Progressive and hierarchical comparisons were conducted to identify which items best discriminated between patients with less severe or more severe disease and healthy volunteers, as well as on which Norfolk QOL-DN domains (symptoms, large fiber, small fiber, autonomic, and ADL) disease stage would have the greatest impact. Eta squared (𝜂 2 ) was calculated as a measure of effect size.
Associations between Norfolk QOL-DN and symptom duration and NIS total score The associations between Norfolk TQOL-DN score and symptom duration and NIS total score were modeled using ordinary least squares regression. Quadratic terms were tested in these models to allow for curvilinearity in the associations.
Results Patient demographics and clinical characteristics The demographic and clinical characteristics of the 61 patients with TTR-FAP and 16 healthy volunteers are summarized in Table 1. As expected, patients with more advanced disease were older, had longer duration of disease, and had a marked deterioration in both NIS-LL and modified body mass index (a measure of nutritional status).
Associations between QOL-DN and NIS-LL subscales Correlations (Pearson’s r) between subjective Norfolk QOL-DN domain scores and objective neuropathy measures were assessed. Objective evaluations of
Exploratory factor analysis All items were screened for floor or ceiling effects as previously mentioned. Two items, electric shocks
Table 1. Patient demographics and disease characteristics at baseline.
Characteristic
Healthy volunteers (n = 16)
Age, mean (SD) years 34.8 (10.0) Men, n (%) 8.0 (50.0) White race, n (%) 16.0 (100.0) Height, mean (SD) cm 169.6 (7.6) Weight, mean (SD) kg 73.8 (17.7) mBMI, mean (SD) 1,199.0 (241.1) Symptom duration, years Mean (SD) NA Median NA Range NA Age at symptom onset, years Mean (SD) NA Median NA Range NA Total NIS, mean (SD) 0.0 (0.0) NIS-LL, mean (SD) 0.0 (0.0) TQOL, mean (SD) 2.6 (5.0)
Stage 1 Independent ambulation (n = 29)
Stage 2 Assistance required to walk (n = 16)
Stage 3 Wheelchair-bound or bedridden (n = 16)
Overall p-value*
39.0 (11.6) 12.0 (41.4) 29.0 (100.0) 165.3 (11.2) 65.5 (13.1) 1,031.9 (213.8)
46.5 (12.8) 9.0 (56.3) 16.0 (100.0) 165.7 (9.4) 62.8 (15.1) 886.4 (309.8)
55.0 (10.0) 10.0 (62.5) 16.0 (100.0) 165.4 (10.1) 54.7 (23.4) 759.7 (316.2)
RESEARCH REPORT
Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy Etta J. Vinik1 , Aaron I. Vinik1 , James F. Paulson2 , Ingemar S. J. Merkies3,4 , Jeff Packman5 , Donna R. Grogan5 , and Teresa Coelho6 1 Eastern Virginia Medical School, Strelitz Diabetes Center, Norfolk, VA, USA; 2 Department of Psychology, Old Dominion University, Norfolk, VA, USA; 3 Department of Neurology, Spaarne Hospital, Hoofddorp, The Netherlands; 4 Department of Neurology, Maastricht University Medical Centre, Maastricht, The Netherlands; 5 FoldRx Pharmaceuticals, Inc., A Wholly-Owned Subsidiary of Pfizer Inc., Cambridge, MA, USA; and 6 Centre for the Study of Amyloidoses, Hospital Santo António, Porto, Portugal
Abstract The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire is an instrument to assess QOL in diabetic polyneuropathy. The objective of this observational, cross-sectional study in 61 patients with V30M transthyretin familial amyloid polyneuropathy (TTR-FAP) and 16 healthy volunteers was to validate the Norfolk QOL-DN for assessment of QOL in TTR-FAP. Comparisons were conducted to identify the best items to discriminate disease stages and assess which individual Norfolk domains (symptoms, large fiber, small fiber, autonomic, and activities of daily living) would be most affected by disease stage. Analysis of individual items revealed a significant pattern of discrimination among disease stages (p < 0.001). Total QOL scores increased (indicating worsening) with duration of symptoms, with a steeper increase observed earlier in the course of disease. Significant correlations were observed between each Norfolk domain and other measures of neurological function. Limitations include cross-sectional study design, low patient numbers in this rare disease, and the ordinal-based character of the metric used; future areas to explore include item response theory approaches such as Rasch analysis. These results suggest the Norfolk QOL-DN is a reliable indicator of the impact of disease severity on QOL in patients with TTR-FAP. Key words: nerve-fiber function, neurological function, Norfolk quality of life, outcome measure, transthyretin amyloid polyneuropathy
Introduction
fibrillar proteins (amyloid) accumulate in tissues in amounts sufficient to impair normal function. A number of different precursor proteins have been associated with familial amyloidosis, including transthyretin (TTR; formerly known as pre-albumin), gelsolin, and apolipoprotein. TTR is primarily synthesized in the liver and circulates in the blood as a transport protein of thyroxine and retinol-binding protein-retinol (vitamin A) complex (Blake et al., 1978; Monaco et al., 1995). In its native state, TTR exists as a homotetramer with two C2 symmetric funnel-shaped thyroxine-binding sites
Systemic amyloidoses encompass both acquired and inherited conditions in which various insoluble
Address correspondence to: Aaron Vinik, MD, PhD, FCP, MACP, FACE, Murray Waitzer Endowed Chair of Diabetes Research, Director of Neuroendocrine Unit, Eastern Virginia Medical School, Strelitz Diabetes Center, 855 W. Brambleton Avenue, Norfolk, VA 23510, USA. Tel: +(1)757-446-5912; Fax: +(1)757-446-5868; E-mail: [email protected]. © 2014 Peripheral Nerve Society
104
Vinik et al.
Journal of the Peripheral Nervous System 19:104–114 (2014)
available (Vickrey et al., 2000; Vileikyte, 2001; Vinik et al., 2005). One such instrument is the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire, which was developed to address the need for a tool to assess patients’ subjective perceptions of symptoms associated with specific nerve fiber damage occurring in DN (Vinik et al., 2005; Vinik and Vinik, 2007; Vinik et al., 2008). This self-administered questionnaire captures patients’ perceptions of a wide spectrum of neuropathy symptoms and is a nerve fiber-specific tool comprising five domains: physical functioning/large-fiber neuropathy, ADL, symptoms, small-fiber neuropathy, and autonomic neuropathy (Vinik and Vinik, 2007). Presence or absence of neuropathic symptoms is recorded, and items assessing ability to perform ADL, as well as generic health status, are rated on a 5-point Likert-type scale, with higher scores indicating poorer status. The Norfolk QOL-DN has been validated in populations with mild-to-severe DPN (Vinik and Vinik, 2007; Vinik and Ziegler, 2007; Vinik et al., 2008) and discriminates DPN patients from healthy controls, shows excellent reproducibility, and can discriminate across different levels of disease severity (Vinik et al., 2005; Vinik and Vinik, 2007; Vinik et al., 2008). The authors have shown previously (Vinik et al., 2005; 2008) that the primary influences on QOL in DPN are physical functioning and ADL, accounting for 59.7% of the variance. Effects on ADL appear to be primarily determined by fine motor functions, in contrast to the greater influence of gross motor requirements for activities in the physical functioning/large-fiber domain. The rapid loss of motor function in the TTR-FAP patient population, resulting in confinement to a wheelchair, clearly would be expected to affect both ADL and physical functioning, with a substantial impact on QOL. The main objective of this study was to assess the validity and reliability of the Norfolk QOL-DN as an index of health-related QOL in patients with the rare disease TTR-FAP. We have evaluated its ability to discriminate between the different levels of TTR-FAP disease severity at early and later stages of disease. We also examined the relationships, by TTR-FAP disease stage, between the Norfolk QOL-DN and objective measures of nerve-fiber function, autonomic function, and impairment due to neuropathy.
located at the central dimer–dimer interface (Nilsson et al., 1975; Saraiva, 2001). While TTR-familial amyloid polyneuropathy (TTR-FAP) is a rare disease with variable penetrance and onset in those carrying a causative mutation, it represents the most common form of familial amyloidosis and is an axonal degenerative disease affecting sensory, motor, and autonomic function that is fatal over an average time of 10 years from symptom onset (Benson, 1989; Planté-Bordeneuve and Said, 2011; Coelho et al., 2013). As this axonal degeneration begins in the distal small unmyelinated fibers involved with pain and temperature sensation, the initial symptoms are hypoesthesia, paresthesia, and loss of sensation in the lower limbs (LLs) (Thomas and King, 1974; Benson, 1989; Planté-Bordeneuve and Said, 2011), in a pattern similar to that observed in diabetic polyneuropathy (DPN) (Boulton et al., 2005; Vinik et al., 2013). As with DPN, progression of TTR-FAP is accompanied by greater involvement of the upper limbs and progression to more extensive motor involvement. The extent to which a patient’s walking ability is impaired is a particularly salient sign of disease progression. The Coutinho classification system for TTR-FAP disease progression utilizes three stages which are based on limb involvement; the disruption of activities of daily living (ADL); the severity of sensory, motor, and autonomic neuropathic dysfunction; and ambulation status (Coutinho et al., 1980). Autonomic neuropathy may be the presenting symptom or it may be seen somewhat later, usually within 1–2 years of disease onset. Symptoms such as nausea, vomiting, constipation alternating with diarrhea, urinary retention or incontinence, anhidrosis, orthostatic hypotension, and sexual impotence may be present (Coutinho et al., 1980). Health-related quality of life (QOL) can be measured by a variety of self-administered questions regarding perceived aspects of physical and mental health and function (McHorney, 1999; Centers for Disease Control and Prevention, 2000). Despite the substantial deleterious impact that TTR-FAP would be expected to have on health-related QOL, there have been very few reports of health-related QOL evaluations in this patient population. Of the studies that have addressed this important issue, most have sought to characterize QOL specifically in patients who have undergone liver transplantation. Nearly all these studies have utilized generic health-related QOL instruments, such as the Medical Outcome Study 36-item short-form survey, which have not been validated in TTR-FAP (Jonsén et al., 1996; Jonsén et al., 2001; Drent et al., 2009). The lack of a specific tool with which to evaluate QOL in TTR-FAP stands in contrast to DPN, for which several validated instruments are
Materials and Methods Study protocol and participants This was an observational, cross-sectional study conducted in 61 TTR-FAP patients with the Val30Met mutation and 16 healthy volunteers who were between 105
Vinik et al.
Journal of the Peripheral Nervous System 19:104–114 (2014)
LL (total score range, 0–88) and combines subscale scores for muscle weakness (range, 0–64), reflexes (range, 0–8), and sensation at the great toe (range, 0–16) (Dyck et al., 1997). The NIS-LL is particularly appropriate for the assessment of early-stage disease (Ziegler et al., 2011). To enhance reproducibility, the average of two successive NIS-LL assessments performed by the same neurologist at least 24 h apart (but within 7 days) was used in the analysis. Quantitative sensory testing was performed utilizing the Computer Aided Sensory Evaluator IV (WR Medical Electronics, Stillwater, MN, USA), a computerized test of sensory threshold determination. Cooling detection threshold (CDT), vibratory detection threshold (VDT), and heat/pain detection threshold (HPDT) of the upper and lower limbs (CDT and HPDT assessed at the dorsum of the foot and hand; VDT assessed at the dorsum of the great toe and index finger) were determined. The heart rate response to deep breathing (HRDB) was assessed only in those patients without pacemakers.
18 and 50 years of age without neurological disease. The TTR-FAP cohort comprised patients with stage 1 disease at baseline who were participants in a phase II/III interventional study (n = 29), in addition to stage 2 (n = 16) and stage 3 (n = 16) patients. All patients were enrolled at a single study center (Hospital Santo António, Porto, Portugal) and the study protocol was approved by the institutional review board. The Val30Met mutation is endemic in Portugal with 90% penetrance. Disease staging of TTR-FAP was based on the criteria established by Coutinho et al. ( 1980) and determined primarily by ambulatory status: stage 1, fully ambulatory; stage 2, required assistance with ambulation; and stage 3, wheelchair-bound.
Measures QOL was measured using the 35-item Norfolk QOL-DN questionnaire (Vinik et al., 2005; Boyd et al., 2011), developed to reflect symptoms associated with damage to various nerve fiber types (Vinik and Vinik, 2007; Vinik et al., 2008). Following interviews with >1,000 patients, specific items were selected to address the symptoms, complications, and impairment of ADL associated with small and large nerve fibers and autonomic nerves. The original 68-item pool was refined into a 47-item questionnaire, which was then evaluated for its discriminatory ability and found to have sensitivity >75% across all domains and specificity between 71% and 90% (Vinik et al., 2005; Vinik and Vinik, 2007). Following assessment of test/retest reliability and psychometric factor analysis, the Norfolk QOL-DN was further refined to 35 items (Vinik and Vinik, 2007). The questionnaire was translated into Portuguese under the direction of the first two authors using forward/backward translation and cognitive debriefing with FAP patients and linguistically validated (Mapi Research Institute, Lyon, France). Study participants completed the Norfolk QOL-DN questionnaire at baseline and 4 weeks later (except for the stage 1 patients, who were not assessed at week 4). List-wise deletion was used to handle missing data. The scoring approach used in this study yielded a possible range for total quality of life (TQOL) scores of −2 to 138. The validity of the Norfolk QOL-DN for assessing the TTR-FAP population was further delineated by correlating it with objective measures of neurological function, evaluated using a modified form of the neuropathy impairment score (NIS) (Dyck et al., 1995; Casellini et al., 2007), the NIS-Lower Limbs (NIS-LL) (Dyck et al., 1997; Bril, 1999), and quantitative sensory testing. The NIS quantifies a neurological examination (total score range, 0 [normal] to 244 [total impairment]), a tool commonly used to assess clinical efficacy in the treatment of neuropathy. The NIS-LL is restricted to the
Analytical methods Prior to the primary analyses of the differences between QOL in TTR-FAP disease stages, all items were screened for floor or ceiling effects, invariance, or other problems that might compromise their utility in further analysis or in practice. Thereafter, several analytical techniques were used. Due to the descriptive nature of these analyses and the small sample size inherent in this orphan disease population, no corrections were made for multiple comparisons.
Exploratory factor analysis As the Norfolk QOL-DN has 35 items scored in five domains, a forced five-factor extraction was used in the initial exploratory factor analysis for the QOL instrument in the TTR-FAP population. Varimax rotation was used to produce a more clearly interpretable factor structure. Exploratory factor analysis was used for the initial statistical approach because it allows identification of the common factors underlying the scale items. However, because the sample size was relatively small compared with standard psychometric studies, additional analyses were also conducted as described in the following sections. Test/retest reliability of the Norfolk QOL-DN in TTR-FAP The reliability of the Norfolk QOL-DN questionnaire has previously been tested in different DPN study populations, including diabetic controls free of evidence of neuropathy and patients with mild neuropathy, as well as healthy controls. The questionnaire was administered at study entry and again 4 weeks 106
Vinik et al.
Journal of the Peripheral Nervous System 19:104–114 (2014)
after the date of entry (Vinik et al., 2005), and was shown to have acceptable test/retest reliability in these populations. The same methodology was used to assess the test/retest reliability of both the Norfolk QOL-DN and its individual domains. Paired t-tests were used to compare the scores collected at study entry and week 4. Patients enrolled in the current interventional study were not retested.
neuropathy were determined for strength, reflexes, and somatosensory function, and the composite NIS-LL was derived as a sum of the scores of the individual components of the examination, as reported by Casellini et al. ( 2006). Objective scores have been shown to correlate with the individual domains of the QOL-DN in DPN and form the basis of criterion validity (Vinik et al., 2005; Vinik et al., 2008).
Measurement of disease progression over time, discriminatory validity, and item discrimination by disease stage Correlations between Norfolk QOL-DN domain scores and time from symptom onset were examined, with the hypothesis that there would be a significant association between disease progression and worsening scores on the Norfolk QOL-DN. Progressive and hierarchical comparisons were conducted to identify which items best discriminated between patients with less severe or more severe disease and healthy volunteers, as well as on which Norfolk QOL-DN domains (symptoms, large fiber, small fiber, autonomic, and ADL) disease stage would have the greatest impact. Eta squared (𝜂 2 ) was calculated as a measure of effect size.
Associations between Norfolk QOL-DN and symptom duration and NIS total score The associations between Norfolk TQOL-DN score and symptom duration and NIS total score were modeled using ordinary least squares regression. Quadratic terms were tested in these models to allow for curvilinearity in the associations.
Results Patient demographics and clinical characteristics The demographic and clinical characteristics of the 61 patients with TTR-FAP and 16 healthy volunteers are summarized in Table 1. As expected, patients with more advanced disease were older, had longer duration of disease, and had a marked deterioration in both NIS-LL and modified body mass index (a measure of nutritional status).
Associations between QOL-DN and NIS-LL subscales Correlations (Pearson’s r) between subjective Norfolk QOL-DN domain scores and objective neuropathy measures were assessed. Objective evaluations of
Exploratory factor analysis All items were screened for floor or ceiling effects as previously mentioned. Two items, electric shocks
Table 1. Patient demographics and disease characteristics at baseline.
Characteristic
Healthy volunteers (n = 16)
Age, mean (SD) years 34.8 (10.0) Men, n (%) 8.0 (50.0) White race, n (%) 16.0 (100.0) Height, mean (SD) cm 169.6 (7.6) Weight, mean (SD) kg 73.8 (17.7) mBMI, mean (SD) 1,199.0 (241.1) Symptom duration, years Mean (SD) NA Median NA Range NA Age at symptom onset, years Mean (SD) NA Median NA Range NA Total NIS, mean (SD) 0.0 (0.0) NIS-LL, mean (SD) 0.0 (0.0) TQOL, mean (SD) 2.6 (5.0)
Stage 1 Independent ambulation (n = 29)
Stage 2 Assistance required to walk (n = 16)
Stage 3 Wheelchair-bound or bedridden (n = 16)
Overall p-value*
39.0 (11.6) 12.0 (41.4) 29.0 (100.0) 165.3 (11.2) 65.5 (13.1) 1,031.9 (213.8)
46.5 (12.8) 9.0 (56.3) 16.0 (100.0) 165.7 (9.4) 62.8 (15.1) 886.4 (309.8)
55.0 (10.0) 10.0 (62.5) 16.0 (100.0) 165.4 (10.1) 54.7 (23.4) 759.7 (316.2)
