Research News

Genome Research Innovation Initiative: Pathology supported genetic testing

Gknowmix links service delivery with health outcomes research – 16 May 2010 is a collaborative research and service delivery reporting engine that allows its users (clinicians, patients, genetic counsellors, laboratories) to capture information relevant to the genes tested; convert this data into knowledge through a logic engine that integrates different data sets as predetermined by the research team, and output this combined wisdom in a format that is accessible to and readable for an intended audience.

A research project entitled “Development and application of a pathology supported genetic assay to assess the impact of hereditary factors on health outcomes in individuals subjected to a wellness screen”, obtained institutional approval under ethics registration number N09/08/224.

This project forms part of the Genome Research Innovation Initiative launched by the Department of Pathology at the Tygerberg Academic Hospital, in April 2008 (Schneider 2009, see article below). The aim is to match disease diagnosis and therapeutic design with the clinical picture, pathology, environmental risk factors and genetic profile of the patient. This process involves the use of the Gknowmix Logic Engine, developed between 2007-2012 with support from the Support Program for Industry Innovation (SPII) and the Innovation Centre of the South African Medical Research Council. A joint research platform has been established in collaboration with Gknowmix, which aims to equip medical scientists to participate in the genetic testing service delivery process.

Medical scientists involved in the development of genetic tests know that there are a sequence of “events” that happens every time a genetic or pathology test, or a set of tests, are requested by a clinician. Tests are performed, results are returned, and as a result of their research, clinicians can use the information to make important decisions that impact the healthcare of their patients. The scientist who studied the disease in question as part of his/her research project knows what the implications of the test results are, which has to be relayed to the patient once it becomes available for clinical use. Sometimes the clinician using the result contact the “scientist behind the test” directly to get clarity on certain aspects. Exchanging information in this way might not be sufficient as the complexity of genetic tests increase. Each test result indicates something the patient in consultation with a clinician can do in the treatment or mitigation of disease. As the number of different tests and amount of information that needs to be explained to the patient grows, so the need grows to be able to present this information to the patient in a way that can easily be read and understood by both the doctor and the patient. While a specific DNA test is required only once in a lifetime, pathology tests that may indicate whether the gene tested is expressed or not, are often used repeatedly to monitor response to treatment and to determine the effectiveness of the intervention strategy that is advised and may partly be based on the genetic findings. Imagine a computer based system that instantly generate reports and does all the administrative work once the test report template, test quote with medical aid tariff codes, pricing, test motivation, etc. have been set up by the scientists and clinicians involved in the research project. This is where Gknowmix comes in as a research outlet for scientists who wish to communicate the test results to the referring clinician through report authorisation, without compromising their capacity to produce scientific knowledge  – PROF MARITHA KOTZE.


GENRED Newsletter – 2 May 2009

Prof Johann Schneider, head of the Department of Pathology in the Faculty of Health Sciences, University of Stellenbosch writes regarding the influence of molecular genetics on the current and future practice of diagnostic pathology as an integral component of clinical health sciences and clinical practice.


Before the 16th century, medical science still adhered to the theories of Galen and there was no information on human anatomy, physiology and understanding of disease processes. New insights in anatomy derived from dissections of the human body in the 16th century, which paved the way for a revolution in the development of medicine at the time of the renaissance. Hermann Boerhaave (1668 -1738) described morphological abnormalities to explain diseases and clinical findings in the 17th century and he realised that clinical medicine was not meaningful without an understanding of the causes of clinical presentations. Giovanni Battista Morgagni (1682-1771), the father of pathology, paid careful attention to macroscopic pathology and accurate correlations with clinical pictures and he realised the link between altered body function and abnormal structure. The invention and continuous improvement of the microscope and new technologies revealed a new world of disease processes at a cellular level and enabled a rapid expansion of knowledge and understanding of disease during the 18th and 19th centuries. Rudolf Virchow (1821-1902) was the first to apply cellular theory in the study of disease and he, through the combination of cellular physiology and morphology with pathology, established applied cellular pathology as the basis of modern medicine.

Numerous ground breaking discoveries and the development of new technologies during the 20th century, resulted in a growing number of new specialties in medicine and pathology, the introduction of modern evidence based medicine and health science, and major advances in our understanding of disease processes and their diagnosis. Diagnostic pathology and laboratory medicine became an essential and integral part of current clinical medicine and patient care. Recent years saw the introduction of numerous new technologies into the routine pathology laboratory, e.g. electron microscopy; immunohistochemistry; flow cytometry; HPLC; mass spectrometry; electrophoresis; genomics; and proteomics.

Diagnostic work-up

The diagnostic process begins with clinical observations and the need for objective and accurate evidence to arrive at a specific diagnosis. Such evidence will frequently include information obtained through the analysis, examination and interpretation of specimens that have been submitted for pathological assessment. The nature of the desired diagnostic or prognostic information as well as the nature of the specimen will determine the specific required expertise in the fields of Anatomical Pathology, Chemical Pathology, Haematological Pathology, Microbiology, Immunology or Virology respectively. Pathology results, similar to genetic testing, are always interpreted within the appropriate context of a particular patient’s clinical picture and other special investigations and a final diagnosis will depend on careful clinicopathological correlation.

Advanced diagnostic techniques and technologies are being used increasingly to stay abreast of expanding clinical requirements, including the confirmation of difficult diagnoses e.g. subclassifcation of lymphomas; the prognostication of patients e.g. with breast carcinoma; the direction of therapeutic intervention e.g. by detection of minimal residual disease in haemopoeitic malignancies or assessment of microbial / viral drug resistance; and the monitoring of quality assurance. Against this background, it is not surprising that molecular pathology emerged as an important field in all the pathology specialties to improve diagnostic accuracy in e.g. tumour pathology; coagulation disorders; dyslipidaemia, cystic fibrosis; premalignant conditions such as familial polyposis and related syndromes; and many more. Through clinicopathological correlation, all pathology results, including results that obtained through molecular genetic applications, are finally interpreted and integrated with the patient’s clinical findings and data from other special investigations. This well-established and standard diagnostic process frequently includes direct liaison between clinicians and pathologists to ensure the initiation of appropriate further management of a particular patient, including genetic and other forms of counselling by appropriately qualified health professionals. Identification of genetic subgroups at risk of drug side effects or with different dietary requirements provides a scientific basis for targeted intervention as opposed to a one-size-fits-all approach.

Early diagnosis, better prognosis

The rapidly expanding global interest in molecular genetic testing for the early detection of disease and the subsequent opportunity for preventative or therapeutic interventions to influence the outcome of a disease, confirms the importance of this new field in healthcare. The need for pathology tests including molecular genetic tests is primarily determined by clinical need as defined by patients’ expectations and clinicians’ demand for relevant information to guide the clinical management of patients, including the prevention of disease through appropriate interventions. Other relevant drivers for laboratory tests include current developments in health science, health economy including medical aid policies, and evidence-based guidelines pertaining to the diagnosis and clinical management of patients.

New initiative: Pathology supported genetic testing

It is against this background that the Department of Pathology at Stellenbosch University launched an initiative to develop pathology supported molecular genetic testing based on an integrated service- and research approach. Many molecular genetic tests are well established in routine pathology practice and such test results are increasingly required by clinicians to determine patient management, e.g. N-myc amplification in neuroblastoma and sub-classification of breast carcinomas using HER2 gene amplification, transcriptional profiling and BRCA1/2 mutation analysis. The Department of Pathology recently acquired high-throughput technology including real-time PCR and DNA sequencing that created the capacity to offer such tests in response to clinical demand and research interests.

Some of these tests, akin to some other non-genetic pathology tests, have not been adequately validated and the scarcity of sound scientific evidence rightfully challenges the ethical and scientific justification of routine application of these tests in clinical practice. However, the growing clinical demand for such tests pertaining to e.g. pharmacogenetics and nutrigenetics – to identify genetic determinants of differential responses to medical treatment and dietary intervention – drives the need to offer such tests in an appropriate clinical context and as part of an integrated pathology-based platform. Such an approach is often a logical addition to and expansion of well-established clinical practice to sub-classify complex diseases into treatable entities. A good example is cardiovascular disease, where correlation between the presence of well-established genetic and lifestyle risk factors and relevant biochemical profiles including an abnormal lipogram, iron status and/or folate/homocysteine levels, could be used to determine gene expression and monitor response to the intervention strategy applied.

Genetic knowledge integration

It is important to develop innovative approaches to risk management of complex multi-factorial diseases, which could be applied in a clinical context where the genetic test results are fully integrated with relevant clinical information and other diagnostic pathology data, in order to provide informed clinicians with adequate information to facilitate patient care. To determine clinical usefulness, careful review of the literature is performed to prevent the use of single nucleotide polymorphisms (SNPs) of uncertain functional significance in genetic tests, following genome wide association studies that may identify risk alleles in the absence of supporting data on relevant metabolic impairments. In order to address the important ethical and scientific issues pertaining to pathology supported gene-based intervention, the information must be captured in a database preferably as part of properly designed and ethical approved research projects that will advance evidence-based medicine.

Numerous and major advances characterised the evolution of modern medicine during the past centuries and brought about many changes to the practice of clinical and diagnostic health care. The rapidly expanding integration and overlapping of traditionally distinctly seperate fields of medicine introduced a new era of interdisciplinary- and team-approaches to clinical practice and patient care. In this regard, clinical human genetics is indeed no exception. Matching the disease diagnosis and therapeutic design with the clinical picture, pathology, environmental risk factors and genetic profile of the patient is a rapidly evolving era that is likely to become increasingly important. Akin to other fields in medicine and in keeping with clinical demand, closer collaboration, integration and liason between clinicians, geneticists, scientists and pathologists are essential to ensure that patients will benefit from the major advances in our growing understanding of the genetic basis of so many diseases, molecular genetics and molecular pathology.

Newsletter: Adrenaline – April 2008

The Department of Patholgy has recently established a new research facility to boost excellence in research, training and relevant pathology services in all pathology disciplines locally, nationally and internationally.

The executive head of the Department, Prof Johann Schneider, says the new facility will be consolidating previously fragmented and often duplicated resources in the various pathology disciplines to create a more efficient, integrated and cost effective academic platform for research, training and appropriate service related functions within the Department – including Anatomical Pathology, Chemical Pathology, Forensic Medicine, Haematopathology, Medical Microbiology, Medical Virology, Immunology and Molecular Pathology.

“Through its close links with pathology and its interaction with clinicians and the allied health sciences, the Pathology Research Facility (PRF) strives towards efficient, cost effective and one-stop support for the training of postgraduate students, research and specific pathology services to meet the demands of niche markets or specific clinical requirements,” Schneider says.

Located on the fourth floor in the FHS Education Building the PRF infrastructure makes provision for:

  • molecular pathology
  • a placement laboratory, and
  • a dedicated laboratory for the diagnosis and research of prion diseases.

While the laboratory is SU-based, it operates in close collaboration with the National Health Laboratory Service (NHLS) and adds value to the limited academic pathology platform that is linked to the NHLS service laboratory and existing university based laboratories at Tygerberg. The facilities and expertise already available in the Department of Pathology including the excellent facilities for molecular pathology in the Medical Virology division, form an integral part of the PRF.

Genome research innovation

Dr Maritha Kotze, well-known molecular geneticist and scientist, recently joined the PRF to promote genome research innovation amongst students, researchers and clinicians. Through her expertise and established networks, the PRF is now able to offer comprehensive diagnostic and risk management tests as part of a service component of research projects, specifically designed to bridge the traditional gaps between human genetics, clinical medicine, diagnostic pathology and other disciplines such as nutrition.

Dr Kotze’s integrative approach to patient care offers a unique package of clinically translated information that can be used by health professionals to optimize the management and well-being of their patients. A wide spectrum of complex medical conditions, ranging from cardiovascular disease and breast cancer to chronic degenerative diseases such as multiple sclerosis and Alzheimer’s disease, are addressed using the so-called Gknowmix genetic knowledge integration system – a newly-developed software program that pools information from different sources. Maritha can be contacted at the Deptartment of Pathology at the Faculty of Health Sciences (tel 021 9389324 / 0828799108).

Training in laboratory techniques

According to Schneider, the PRF supplements the NHLS Service Laboratory and supports the teaching and training of registrars, scientists and technologists in various aspects of pathology that are not available or adequate in the routine service laboratories. As from 2008, the PRF will offer training in laboratory techniques to HonsBScMedSc (Pathology) students. The facility also supports two PhD students and collaborates closely with postgraduate students and researchers from the Faculty, other academic institutions and the private sector. Specific training in molecular pathology techniques is available to students and research assistants from elsewhere.

Molecular-based tests for diagnostic pathology

Only prion laboratory in Africa

Prof Schneider says the renewed global interest in prion diseases created a unique opportunity to establish a dedicated prion laboratory in the PRF through close collaboration between Prof Richard Hewlett from the Neuropathology Unit and Prof James Ironside the National Creutzfeldt-Jakob Disease Surveillance Unit at the University of Edinburgh, United Kingdom. This laboratory is the only one in Africa and will serve as a referral laboratory for specimens from patients with prion disease. Relevant molecular tests including Western blotting will soon be available to enable accurate diagnosis and research into this neglected group of diseases in the African context.

Placement laboratory for specific research demands

The PRF also offers a placement laboratory that caters for specific research demands related to any of the disciplines in pathology, including Anatomical Pathology, Chemical Pathology, Hematopathology, Medical Microbiology, Medical Virology, Immunology, and Forensic Medicine. Depending on the nature of the project, equipment and support can be established to meet the specific requirements of the researcher or project. The PRF can outsource tests when required in terms of a particular project or the needs of a researcher. A small procedure room is available for procedures such as fine needle aspiration biopsy and collection of blood samples. Interested clinicians and researchers can contact Prof Rajiv Erasmus (021 9384107 / or Prof Johann Schneider (0219384041/

  • Accreditation of the PRF laboratory is in progress. The accreditation process will be partly driven by the demand for specific tests or research requirements. The PRF, together with the NHLS service laboratories at Tygerberg, will be assessed later this year by the HPCSA for accreditation as a training facility for medical scientists in the respective pathology disciplines. Through the PRF, the Department of Pathology already established collaboration with other academic institutions and the private sector. Such collaboration will expand the PRF’s capacity to offer unique services and support that meet the demands of niche markets and research projects – printed with permission, SYBEL ALBRECT.