LETTERS TO THE EDITOR
Classification and codification of rare diseases
To the Editor:
Rare diseases (RDs) are a group of disorders of very dif-
ferent etiology, whose common denominator is that they are
low-prevalence diseases and for most of which there is no
treatment available. Because of their low prevalence, they
attract little interest from basic and clinical researchers
and the scientific community in general, all of whom find
it very difficult to secure public and/or private sources of
financing for the study of the pathogenesis, diagnosis, and
treatment of such diseases [1].
There is no unique definition of an RD. Currently the
definition of RDs is found in orphan drug legislation, which
provides incentives for the development of medicinal prod-
ucts for diseases that may otherwise suffer from nonviability
of the market. Through the US Orphan Drugs Act, the United
States was the first country to provide an operational defini-
tion of RD: ‘‘A disease is considered rare when it affects less
than one per 1,250 individuals in terms of prevalence’’ [2].
The European Parliament adopted a stricter definition:
‘‘A condition is considered rare when it affects less than
one per 2,000 individuals’’ [3]. The Japanese Orphan Drugs
Act considers a rare disorder to be any disease afflicting
fewer than 4 per 10,000 inhabitants. The Australian orphan
drugs legislation lays down that a rare disorder is one that
affects fewer than 1 in 10,000 Australians [1]. This statistical
definition of rare disorders was viewed as an answer to the
pharmaceutical needs to increase the investments in new
drug research for the treatment of such diseases [4].
Whichever threshold is used, however, RDs have several
characteristics: most have genetic origins, but a significant
number are acquired with the contribution of environmental
factors; onset occurs in about half of them at birth or during
infancy, whereas the rest appear during adulthood; RDs are
often associated with premature mortality and long-lasting
and severe disability [5,6]. Each disease affects a small num-
ber of patients, but these conditions are numerous and collec-
tively affect a high number of persons. It is estimated that
today in the European Union, 5 to 8,000 distinct RDs affect
6% to 8% of the populationdbetween 27 and 36 million
peopledwhich make RDs a priority at the European level
in the field of public health [7]. To prioritize limited public
health resources it is important to possess reliable data on dis-
ease burden, course of disease, and long-term prognosis. This
has been a difficult task for RDs. A primary reason why sound
epidemiological data are often lacking is the absence of
proper classification and coding for the disease. Problems
with coding can have a major impact on RDs as even a small
number of inappropriately coded cases can greatly influence
frequency distribution and rate. Adequate definition/
codification of RDs is a priority action at the European level
to ensure that RDs are adequately coded and traceable in all
health information systems based on the International Classi-
fication of Diseases (ICD) [8]. A specific working group on
RDs has been set up by the European Commission to collab-
orate with the World Health Organization, in the process of
revision of the 10th version of ICD to adopt a new 11th ver-
sion [9]. The aim is to improve the classification of them in
the ICD and codify them to the highest degree of accuracy
and completeness. Because the process of classification and
codification is the translation of disease diagnosis into
a code, it depends on the accuracy of medical diagnosis, dis-
ease terminology, and the selection of classification system.
The medical diagnosis of RDs is a difficult task because
of the lack of knowledge and deficient diagnostic systems.
Moreover, the terminology of RDs differs greatly from the
ICD language. Most terms describing RDs are eponyms,
which should be avoided because they are not self-descriptive.
The difficulties of classifying RDs can also be attributed
to the inadequacy of the current system of classification.
ICD codes are still not sufficiently precise for many RDs,
although ICD codes are available for some of the better-
known RDs. Often RDs are grouped under higher classifi-
cation levels [10]. Most RDs are genetic in origin, and
the ICD system classifies the disease according to the phe-
notypes alone and does not categorize them according to
genetic abnormalities. There is a need for a classification
that is capable of reflecting the multidimensionality of dis-
eases [11]. The future version of the ICD should satisfy
these criteria.
Yllka Kodra
National Centre for Rare Diseases
Istituto Superiore di Sanit
a
Viale Regina Elena 299
00161 Rome, Italy
Corresponding author.
Tel.: þ39-06-49904365; fax: þ39-06-49904370
E-mail address: yllka.kodra@iss.it
Conflict of interest statement: The authors have no conflict of interest to
declare.
0895-4356/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved.
Journal of Clinical Epidemiology 65 (2012) 1026e1028