Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-A successful strategy for clinical research of rare diseases

Abstract

Background: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts.

Aims: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs.

Methods: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases.

Results: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients.

Conclusions: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.

Keywords: Urea cycle Disorders; diagnostic methods; international registry and database.

Fig. 1

Mosaic plot of the association of diagnoses with geographical region. The height of the boxes in a row represents the proportion of a particular diagnosis. The widths of two boxes in a row represent the proportions of individuals with a particular diagnosis in each of the two geographic areas; i.e. the North American (left) and the European sample (right). Significance disappeared after exclusion of fOTC-D, particularly asfOTC-D (for details see text).

Fig. 2

Mosaic plot of the association of diagnoses, type of onset, and geographical region. The upper part illustrates early onset (EO), the lower part late onset (LO). The height of the boxes in a row represents the proportion of a particular diagnosis. The widths of two boxes in a row represent the proportions of individuals with a particular diagnosis in each of the two geographic areas; i.e. the North American (left) and the European sample (right) (for details see text).

Fig. 3

Modes of diagnosis and their distributions over five decades from 1971 until 2016. SX, Selective metabolic investigation after onset of symptoms; FH, Family history triggered investigation; NBS, Newborn screening; PT, Prenatal testing.

Fig. 4

Mosaic plot of the association of methods used for confirmation before 2005 and afterwards in the combined sample of UCD and E-IMD patients. In both geographic regions there is a clear shift from using metabolites and enzymes to mutation analysis.