SUS to incorporate Exoma sequencing to diagnose intellectual disability

BRAINN - Joana Prota e Iscia Lopes-Cendes Exoma no SUS
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Decision to adopt the exam was guided by a technical-scientific opinion prepared by a doctorate from FCM-Unicamp, working with researchers from CEPID BRAINN.

April 10th 2019  | originally published at Jornal da Unicamp

Scientific researches held at universities of excellence such as Unicamp produce several positive impacts for society. These include the generation of new knowledge, the training of qualified human resources and the development of innovative processes and technologies. In addition to these results, such studies can also contribute to the formulation of public policies that directly benefit the citizen, as is the case of the doctoral work of the geneticist Joana Prota, who is oriented by Professor Iscia Lopes-Cendes and co-oriented by Professor Antonia Paula Marques de Faria, both of the Department of Medical Genetics and Genomic Medicine of the Faculty of Medical Sciences (FCM). Based on her research, and in a parallel work carried out under the coordination of her co-supervisor, with the participation of Professor Carlos Eduardo Steiner, the doctoral student prepared a technical-scientific opinion that culminated in the incorporation, by Brazil´s Unified Health System (SUS, in Portuguese) of the Exoma sequencing [genome fraction] for etiological investigation of intellectual disability of undetermined cause.

The ordinance that led to the adoption of the examination by the SUS was published in the Federal Official Gazette on March 29. Exoma sequencing is an outpatient procedure of high complexity, which should be performed by reference centers. “It is always an additional satisfaction when we have the opportunity to contribute, from our research, to the formulation of public policies that seek the welfare of society”, says Professor Iscia. The objective of Joana’s doctoral work, which is still underway, is to evaluate the cost-effectiveness of the Exoma test, in addition to seek scientific evidence to justify the incorporation of the procedure by SUS.

The opportunity to elaborate a technical-scientific opinion that evaluated the test in the etiological investigation of the intellectual deficiency of undetermined cause arose with its participation in the work group constituted in 2015 – based on indications of the Brazilian Society of Medical and Genomic Genetics to the National Commission of Technology Adoption (CONITEC) – , to develop the “Clinical Protocol and Therapeutic Guidelines (PCDT) – Etiological Diagnosis of Intellectual Disability, coordinated by Professor Antonia Paula. Since the Exoma test is included in the PCDT’s intellectual disability research algorithm, but was not among the exams incorporated by SUS, it was necessary that the technical-scientific opinion be submitted to the CONITEC plenary. With the approval of the indication, PCDT should be finalized and included among the “Guidelines for the Comprehensive Care of Persons with Rare Diseases in the SUS”, as part of the measures to implement the Health Ministry’s “National Policy for Comprehensive Care for Persons with Rare Diseases”.

In the doctoral project, the medical geneticist made the sequencing of Exoma, which corresponds to 2% of the human genome, of 70 individuals, divided into two groups. One segment brought together people with intellectual deficits and the other, people with dementia, movement disorders and other genetically determined diseases, but with different inheritance patterns. “Because they are different diseases, it is expected that the Exoma also presents variation in the diagnostic yield, according to the problem. It is noteworthy that we must understand by ‘yield’ the ability of the test to identify the genetic changes, ie how many patients the procedure is able to diagnose within a given contingent”, explains the geneticist.

Currently, Joana continues, the SUS adopts two genetic tests to investigate the intellectual deficiency: the chromosomal microarray and the karyotype, and the first one has not been effectively implemented by the system. In comparison with karyotype, Exoma showed a significantly higher yield: 40% versus 3%. In other words, while the karyotype is able to identify three cases of change in every 100 patients submitted to the test, Exoma identifies 40. Regarding microarray, which is already included but not yet available in most services, the yield is around 10% to 20%. In addition, Joana proved that, because it is more effective, each patient diagnosed with Exoma, even with a higher nominal cost, ends up generating a lower final cost, since Exoma has a higher diagnostic yield.

Professor Iscia further clarified that the technical-scientific opinion prepared by Joana was based on a secondary study, which took into account data from the literature referring to research carried out in other countries on the same subject, but that the studies made in the scope of the thesis of Joana confirm these findings in the Brazilian population. “With this, the arguments are much more robust, since they demonstrate that the results recorded in the literature are also reproduced locally. It was the consistency of this set of arguments that led the CONITEC Plenary to decide on the incorporation of the procedure, which leaves us very satisfied”, says the professor.

Asked about the challenges to implement the Exoma test in SUS, Professor Iscia assures that difficulties can be overcome with organization. She notes that the State of São Paulo, for example, has several institutions, among them universities, that have the instruments to carry out the tests. “These laboratories, including ours here at Unicamp, could provide this service to SUS, provided they were adequately remunerated. Here, we could incorporate this demand into our routine, so as not to hinder research activities”, she says.

Outside of São Paulo, the teacher acknowledges, the difficulties tend to be somewhat greater, but they can also be circumvented, since the laboratories of São Paulo would be able to meet part of this demand. “I think that, with planning, it is possible to offer this examination to the population as it appears in the ordinance”, she adds. Currently, according to the author of the doctoral thesis, the prevalence of intellectual disability in the general population ranges from 1% [developed countries] to 2% [developing countries]. In the case of Brazil, this percentage is equivalent to about 4 million people, a number close to that of the population of Espírito Santo.

With the advent of the test, according to Professor Iscia, the trend will be to soften what experts classify as “diagnostic odyssey”, which is the protracted search by parents for an explanation on the origin of their children’s intellectual disability. “During this process, expensive tests are usually done and may not contribute to this identification. In addition to overloading the public health system, this causes a great deal of anxiety for parents”, says the FCM professor.

Although it is fundamental, the knowledge accumulated by Medicine is not the only one employed in this type of research. Due to its complexity, the theme requires a multidisciplinary approach. An important factor in this aspect is the support provided by mathematics, more specifically by statistics, that develops algorithms that make the analysis of genetic mutations. “In this sense, we count on the valuable collaboration of Professors Benilton de Sá Carvalho and Tatiana Benaglia, both from the Statistics Department of IMECC [Institute of Mathematics, Statistics and Scientific Computing]”, emphasizes Professor Iscia.

For Professor Tatiana, integrating a project that has contributed to the formulation of a public policy that will benefit society is extremely rewarding. “It serves as a stimulus to continue seeking answers to the problems of the population. In this case, we also offer evidence that can help public managers better apply the available resources. By calculating the cost-effectiveness of the exam, we have been able to demonstrate that not everything that seems to be cheaper is really so in the long run”, she says.


Read the full article on the Jornal da Unicamp website


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