Alkaptonuria Severity Score Index Revisited: Analysing the AKUSSI and Its Subcomponent Features

Abstract

Background: Alkaptonuria (AKU) is a rare disorder with no licensed treatment; nitisinone may reduce symptoms and progression. The All Alkaptonuria Severity Score Index (AKUSSI) measures disease severity in clinical, joint and spine domains, with 57 subcomponent feature scores. Our primary aim was to assess tools for validating scores such as the AKUSSI by detecting relationships between features both before and during nitisinone treatment.

Methods: AKUSSI measurements from nitisinone-treated patients visiting the National AKU Centre between 01-Jun-2012 and 31-May-2016 were analysed pre-treatment, at first treatment and annually to Year 3 post-treatment. Principal component analysis (PCA) and redundancy analysis assessed whether any AKUSSI features contributed little information to the overall score.

Results: 65 AKU patients were included: 17 with a pre-treatment AKUSSI measurement (10 later received nitisinone) and 48 with a first measurement at their first treatment visit. In PCA, the first four principal components (PC1-PC4) explained ≥50% of AKUSSI variance at all visits (54.1-87.3%). Some features regularly dominated their domain's PC1: ears, aortic sclerosis, and nasal/temporal eye scores (clinical), pain-related scores (joint) and cervical, lumbar and thoracic spine scores (spine). Only the right-hand/wrist score was consistently redundant. Right eye (nasal) and left ear scores were redundant pre-treatment, potentially correlating with other dominant clinical PC1 features.

Conclusions: PCA and redundancy analysis supported the AKUSSI as a robust AKU disease severity measure, although some AKUSSI features could be removed for simplicity. For small patient populations and rare diseases, PCA and redundancy analysis together can aid validation of disease severity metrics.

Keywords: Alkaptonuria; Assessment; Efficacy; Nitisinone; Ochronosis; Severity.

Fig. 1

Patient flow diagram and baseline characteristics. ^*Three patients had multiple Pre-NAC measurements; only their initial Pre-NAC visit was included in this analysis. ^†n = 57 patients had Year 0 HGA and tyrosine measurements. AKU alkaptonuria, AKUSSI AKU severity score index, IQR interquartile range, HGA homogentisic acid, NAC National Alkaptonuria Centre, NR not reported, SD standard deviation, SE standard error

Fig. 2

Feature prominence in PCA for the A) clinical domain, B) joint domain and C) spine domain. [a] Proportion of the variance of the data at that visit explained by the given principal component. [b] Proportion of the individual principal component’s variance explained by the given feature. Lighter rectangles denote a larger proportion of the variance; darker rectangles are features which do not contribute much to the variance; there is little difference between patients. CLIN clinical, JNT joint, PC principal component, PCA principal component analysis, SPN spine