Diagnosis of Coronary Artery Disease using NMR-based metabonomics
In 2000, in collaboration with Prof. Nicholson and Dr Elaine Holmes at Imperial College, and Dr. Peter Schofield at Papworth Hospital NHS Trust, we performed a pilot study to determine whether metabonomics could be used to diagnose coronary artery disease (CAD). We selected CAD for this study, for a number of reasons, but most importantly was the lack of any rapid, inexpensive diagnostic procedure. At present, a firm diagnosis of CAD can only be obtained through an invasive procedure called coronary angiography, in which X-ray opaque dye is injected directly into the coronary arteries through a catheter inserted into the groin. Images taken with an X-ray camera directly visualise the blood flow through the arteries and allow blockages, due to CAD, to be identified. Unfortunately, this process is expensive, unpleasant for the patient and can, in a small fraction of patients, lead to side-effects which range from bleeding at the catheter insertion site (in as many as 1 in 100 cases) to more severe morbidity such as stroke, kidney failure or even death (in some 1 in 1000 cases).
For our pilot study, which was published recently (Nature Medicine 8:1439), we took blood samples from approximately 40 people with severe heart disease (identified by angiography) and compared them with 40 people with normal coronary arteries. Simple one-dimensional proton NMR spectra were collected and subsequently analysed using PCA and PLS-DA. Simple PCA revealed clustering of the profiles into two groups, but did not completely separate the groups in the way you would need to achieve to make a clinically useful diagnosis. However, application of a single round of OSC (orthogonal signal correction), resulted in almost perfect separation. The PLS-DA model built on the OSC-transformed dataset was then validated by several different mathematical approaches. This model could be used to predict the CAD status of individuals who are yet to have an angiography.
Considerable public interest followed the initial publication of this data in November 2002, driven by the expectation that a metabonomics based test might be able to replace at least some applications of coronary angiography. Before such expectations can be met, however, a large scale clinical trial is required. Such a trial is now running out of Papworth Hospital, termed the MaGiCAD study. Our laboratory is working with Metabometrix Limited and FingerPrint Diagnostics Limited to bring a commercial test based on this new technology to the clinic by 2005.