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Latent Class Analysis to Classify Patients with Transthyretin Amyloidosis by Signs and Symptoms

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Latent Class Analysis to Classify Patients with Transthyretin Amyloidosis by Signs and Symptoms Neurol Ther DOI 10.1007/s40120-015-0028-y ORIGINAL RESEARCH Latent Class Analysis to Classify Patients with Transthyretin Amyloidosis by Signs and Symptoms Jose Alvir . Michelle Stewart . Isabel Conceic¸a˜o To view enhanced content go to www.neurologytherapy-open.com Received: February 21, 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com ABSTRACT status measures for the latent classes were examined. Introduction: The aim of this study was to Results: A four-class latent class solution was develop an empirical approach to classifying thebestfitforthedata.Thelatentclasseswere patients with transthyretin amyloidosis (ATTR) characterized by the predominant symptoms based on clinical signs and symptoms. as severe neuropathy/severe autonomic, Methods: Data from 971 symptomatic subjects moderate to severe neuropathy/low to enrolled in the Transthyretin Amyloidosis moderate autonomic involvement, severe Outcomes Survey were analyzed using a latent cardiac, and moderate to severe neuropathy. class analysis approach. Differences in health Incorporating disease duration improved the model fit. It was found that measures of health Electronic supplementary material The online status varied by latent class in interpretable version of this article (doi:10.1007/s40120-015-0028-y) contains supplementary material, which is available to patterns. authorized users. Conclusion: This latent class analysis approach On behalf of the THAOS Investigators. offered promise in categorizing patients with ATTR across the spectrum of disease. The four- Trial registration: ClinicalTrials.gov number, class latent class solution included disease NCT00628745. duration and enabled better detection of J. Alvir (&) heterogeneity within and across genotypes Statistical Center for Outcomes, Real-World and than previous approaches, which have tended Aggregate Data, Global Medicines Development, Global Innovative Pharma Business, Pfizer, Inc., to classify patients a priori into neuropathic, New York, NY, USA cardiac, and mixed groups. Although this study e-mail: Jose.Alvir@pfizer.com utilized a cross-sectional approach to disease M. Stewart duration, future work could include the Pfizer, Inc., New York, NY, USA application of longitudinal latent class I. Conceic¸a˜o analyses. Department of Neurosciences, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Funding: Pfizer Inc., New York, NY, USA. Portugal Neurol Ther Keywords: Amyloidosis; Cardiomyopathy [4]. Even within the most common TTR Latent class analysis; Polyneuropathy mutation, V30M (valine is replaced by Transthyretin methionine at position 30), there is a tremendous heterogeneity of presentation INTRODUCTION [5, 6]. Classification by genotype has largely been focused on the distinction between the Transthyretin amyloidosis (ATTR) is a most common variant, V30M, and other progressive, degenerative disease. In familial mutations that are often lumped together into ATTR, a single gene mutation leads to one non-V30M group, and the wild-type group. instability and dissociation of the TTR Another a priori approach to classification of tetramer, leading to amyloid formation. Wild- patients with ATTR that has been widely used type TTR can de-stabilize with advancing age classifies them into neuropathic, cardiac, and and also lead to amyloid formation. mixed (with features of both neuropathy and Two common sites of amyloid deposition are cardiomyopathy) groups based on their peripheral nerves and the heart. Typical early phenotypic presentation, regardless of their neuropathic symptoms are paresthesias, sensory genotype. deficit, and distal neuropathic pain with a Until now, little empirical research has been distal–proximal progression. Deposition in the undertaken to develop a classification scheme myocardium leads to diastolic dysfunction, for the full spectrum of patients with ATTR. In restrictive cardiomyopathy, arrhythmias, and this study, we grouped patients with heart failure. Autonomic neuropathy including symptomatic ATTR based on their clinical signs erectile dysfunction, bladder paresis, postural and symptoms using latent class analysis (LCA) hypotension, and gastrointestinal symptoms [7, 8] and explored the relationships between such as nausea, constipation, and diarrhea latent class (LC) membership and clinical may also occur [1, 2]. measures. The primarily neuropathic and cardiac phenotypes are known as transthyretin METHODS familial amyloid polyneuropathy (TTR-FAP) and transthyretin cardiomyopathy (TTR-CM), Standard Protocol Approvals, respectively. However, cardiac involvement is Registrations, and Patient Consents not uncommon in TTR-FAP, especially in later stages, and neuropathy can appear in patients The Transthyretin Amyloidosis Outcomes with TTR-CM [3, 4]. Both groups can experience Survey (THAOS; ClinicalTrials.gov number, autonomic symptoms. NCT00628745) is a longitudinal, observational Attempts to classify patients based on registry of symptomatic patients with ATTR genotype have limitations. There is significant (familial and wild type) and asymptomatic overlap in presenting symptoms and various mutation carriers. One of its principal aims is mutations have been classified on a ‘‘spectrum’’ to better understand and characterize the ranging from predominantly neurologic to natural history of the disease by studying a predominantly cardiac, with mixed large and heterogeneous patient population. presentations involving varying degrees of both The design and methodology of THAOS, neurologic and cardiac symptoms in between including data collection and assessments, are Neurol Ther described elsewhere [9]. Approval from local autonomic dysfunction) that adjusts for serum Ethical Review Board/Institutional Review albumin concentration, was calculated by Board was obtained, all participants provided multiplying BMI (kg/m2) by serum albumin written informed consent, and use of THAOS concentration (g/L). The frequency of erectile data for this study was approved by the THAOS dysfunction and depression was also examined. Scientific Board. The Karnofsky Performance Status is a clinician-rated assessment of functional Patients impairment with scores ranging from 0 (dead) to 100 (normal functioning/no disease). The This analysis included symptomatic patients Karnofsky scores at enrollment were analyzed participating in THAOS as of June 2013. and patients were categorized as unable to care Patients who had liver or heart transplantation for self (scored 0–40), unable to work but able to prior to enrollment were excluded. self-care (scored 50–70), and able to accomplish normal activities and work (scored 80–100). Clinical Signs and Symptom Data Patients completed the European Quality of Life-5 dimension-3 level (EQ-5D-3L) Signs and symptom data collected at THAOS instrument, a standardized measure of health enrollment were used. Individual signs and consisting of five items to rate Mobility, Self- symptoms were dichotomously coded as care, Ability to perform usual activities, Pain/ ‘‘present’’ if assessed as possibly or definitely discomfort, and Anxiety/depression on a 0 (not related to ATTR or ‘‘absent’’ if absent or deemed a problem) to 2 (unable to do/extreme problem) not related to ATTR. In total, 27 signs and scale. Patients’ responses were analyzed by item symptoms reported for at least 5% of the and used to calculate the EQ-5D-3L Index score. patients were included in this study. Patients’ rating of their current health (using the sixth item, Health State, with 0 as the worst Other Measures and 100 the best imaginable health state) was also analyzed. Demographic and clinical variables were examined. Of particular importance was ATTR Statistical Analysis disease duration, defined as the time since occurrence of the first ATTR symptom. Latent class analysis [7, 8] is a statistical method Patients were categorized by disease duration used to find LCs (subgroups or natural taxa) \4 and C4 years, a cutoff value close to the using categorical data. Generally applied in median, therefore resulting in similar numbers social and behavioral science research, it is an of patients in each category. extension of work pioneered in psychology that Physical examination measures included posits unobservable (latent) structures underlie change in supine-to-standing blood pressure observable or manifest psychological (BP) and the presence of orthostatic phenomena [10–12]. LCA classifies individuals hypotension (systolic BP decline[20 mmHg or into mutually exclusive LCs and assumes that diastolic BP decline[10 mmHg). The modified all variables are independent within each LC; body mass index (mBMI), a marker of thus, the LC explains the associations among nutritional status (especially in patients with the observed variables (e.g., symptoms). Two Neurol Ther sets of parameters are estimated by LCA: class mean age ± standard deviation (SD) was membership probabilities and item response 53.5 ± 18.0 years. Males comprised 60% of the probabilities within each LC. Each individual sample. The median ATTR duration was has a set of posterior probabilities, equal to the 3.33 years, with mean ± SD of 5.6 ± 6.7 years, number of LCs in the model. Individuals are and 57% had ATTR duration\4 years. Time assigned to LC with the highest posterior since diagnosis was available for 608 patients probability. with a mean ± SD of 1.8 ± 2.8 years. As recommended, we fit an initial set of models, specifying two to six LCs, without any Latent Class Analyses grouping variable or covariates [13]. The adjusted
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