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Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS) Post Treatment Lyme Disease Syndrome (PTLDS), Fibromyalgia Leading Research. Delivering Hope.Open Medicine Foundation® Canada
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Preprint: A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study

The Heart of the Matter

  • OMF’s Computational Research Center and the ME/CFS Collaborative Center at Stanford University have released a preprint of their work investigating the pathogenesis of ME/CFS using data from the severely ill patient study (SIPS). 
  • Using a network medicine approach, the team created a SIPS disease module that showed strong interplay with immune and neurological conditions and included a significant presence of genes associated with fatigue and cognitive disorders. 
  • The SIPS disease module showed overlap with two other ME/CFS cohorts, indicating a potential genetic contribution to ME/CFS pathogenesis across cohorts.
  • The modified metabolic networks indicate that an altered immune system response and oxidative stress contribute to the pathophysiology of ME/CFS.
On the left is a picture of Dr. Ron Davis, who has white hair, glasses, and a beard, and is smiling while wearing a light blue shirt. On the right is a picture of Dr. Wenzhong Xiao, who has black hair and is wearing a dark suit jacket over a light-colored shirt.

A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study

Open Medicine Foundation’s Computational Research Center and the ME/CFS Collaborative Center at Stanford University have released a preprint of their work studying the pathogenesis of ME/CFS in severely ill patients. The severely ill patient study (SIPS) included 20 patients exhibiting severe symptoms of ME/CFS, and this particular research approach utilized whole genome sequencing on blood samples from the project.

This study uses a network medicine approach to identify potential genetic contributions to the mechanisms of ME/CFS. In this kind of approach, a disease module is a way of describing the genes and pathways that are causing problems in patients with that disease. These disease modules are fit into the human PPI network, which is a holistic picture of protein-protein interactions (PPI) in the body, and can therefore be compared or connected to disease modules of other similar diseases. One benefit of a computational, network medicine approach like this is the ability to pull together information from different sources to identify commonalities that may help explain complex problems.

The SIPS disease module was developed from an initial set of 103 pathogenic or likely pathogenic variants identified from the whole genome sequencing. After exploring the connections between relevant genes and symptoms of ME/CFS, the team identified a significant presence of genes associated with fatigue and cognitive disorders – genes related to fatigue were enriched 3.94-fold, and those connected to cognitive disorders were enriched 2.29-fold. 

In addition, when looking at the interplay of the SIPS disease module and other disease modules, there was notable interaction with six neurodegenerative disease pathways. Overall, the most similar diseases identified through this network medicine approach were immune and neurological conditions. These findings match the results of disparate studies, providing strong evidence to support data that is otherwise siloed and helping to develop a cohesive hypothesis for the development of ME/CFS.

To further investigate the pathogenesis of ME/CFS, the study team then cross-referenced the SIPS disease module with two other datasets, containing two ME/CFS cohort disease modules and one disease module for a depressive disorder cohort. The SIPS disease module has about 40% overlap with the other ME/CFS cohorts, but minimal overlap with the depressive disorder cohort. This suggests there might be shared genetic factors that contribute to the development of ME/CFS across cohorts and provides further evidence that conflating ME/CFS with depression is incorrect.

Finally, the study team extended these results by identifying individual pathways that may contribute to the development of ME/CFS. The top pathways they identified align with findings from various studies, which ultimately provides strong evidence that immune dysregulation is part of the pathogenesis of ME/CFS.

Read the full preprint here.

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Microvesicles and viral sequencing
Microvesicles are a type of extracellular vesicle that is released from the cell membrane. Vesicles are small, fluid-filled sacs or vacuoles within the body. Sequencing is a technique used to determine the exact sequence of bases (A, C, G, and T) in a DNA (or viral) molecule.
NMR Metabolomics
NMR (Nuclear Magnetic Resonance) is an instrument/tool used to perform metabolic studies, metabolic profiling, and metabolomics in biofluids and tissues for more than 40 years using magnetic fields. There is a very close connection between metabolic measurements and NMR. This connection has flourished because of NMR’s many unique strengths for characterizing complex mixtures’ chemical composition.
Proteomics
The large-scale study of proteins, which are large, complex molecules that are required for structure, function, and regulation of the human body's tissues and organs.
Autoantibodies
Antibodies that react with self-molecules and that occur in healthy individuals and are referred to as natural antibodies or autoantibodies.
Extracellular DNA for viral reactivation and Mitochondrial DNA
exDNA (extracellular DNA), exDNA is often secreted actively and is used to perform several tasks, thereby offering an attractive target or tool for biotechnological, medical, environmental, and general microbiological applications. Viruses are intracellular parasites that rely to a significant extent on the host cell for replication. Viral reactivation occurs when an active replication of the viral genome results in a lytic (degradation of the cell) infection characterized by the release of new progeny (descendant) virus particles.
Immune cell profiling
The immune system has many important regulatory roles in disease development and progression. Given the emergence of effective immune therapies, reliable predictors of response are needed. Immune cell profiling determines response by evaluating immune cell populations from treated and untreated samples. For our purposes, we will evaluate the white blood cell response to the viral infection using a process called “Cytof.”
Leukocyte Genomics
A leukocyte is a colorless cell circulating in the blood and body fluids and is involved in counteracting foreign substances and disease. A genome is all genetic material of an organism. Genomics is a biology field focusing on the structure, function, evolution, mapping, and editing of genomes. Therefore, leukocyte genomics is the study of all genetic material of leukocytes.
Metabolomics
Metabolomics is a way to study metabolism – that is, through measuring amounts of the metabolites (small molecules) produced by our bodies as we convert food into energy and other molecules that our cells need to survive. Metabolomics technology is ‘large-scale,’ meaning that several thousand metabolites can be measured from a single sample of e.g., blood or urine.
Micro RNA
Cells use Micro RNA to control whether a particular gene is making too much, too little or the normal amount of its protein at a particular time.