Identifying predictive and prognostic biomarkers for Crohn’s disease

Highlights from live Olink-sponsored workshops in Boston.

Olink sponsored a pair of live, in-person events in Boston MA, and in San Diego CA recently, where topics ranged from the increased risk of dementia in HIV-infected patients to research looking for new Alzheimers Disease biomarkers in the cerebral-spinal fluid of affected individuals.

Dr. Andres Hurtado-Lorenzo is the Vice President of Translational Research of the Crohn’s and Colitis Foundation, based in New York, where he sponsors a wide variety of projects with direct impact on the treatment and detection of Crohn’s Disease and ulcerative colitis.

The Unmet Need of Crohn’s Disease and Irritable Bowel Disease

Dr. Hurtado-Lorenzo began with the wide heterogeneity of this condition: some individuals are stable with treatment, others have periodic flares, and still, others have a chronic condition. IBD is characterized by segmental inflammation and diarrhea, while ulcerative colitis is known for diffuse inflammation of the colon and rectum with cramping and urgency a common complaint.

The treatment options are limited, and 40% of those who undergo surgery do not respond to medication (anti-TNF therapy). Of those who do respond, another 30% of those lose this response.

He showed a diagram of three different forms of severity within Crohn’s Ileitis: B1 (‘inflammation’), B2 (‘stenosis and distended ileum’), and B3 (‘Fistula formation’ with the sigmoid colon). In B3 disease, there are structures called strictures, or narrowing of the intestines due to continuous cycles of inflammation and healing of the intestinal lining. As a result, scar tissue builds to narrow, and sometimes obstruct areas of the bowel.

His research goal was to determine prognostic markers for B2 and B3 disease (that is, to predict the disease course).

Dr.Hurtado-Lorenzo-presentation

Dr. Andres Hurtado-Lorenzo, Vice President of Translational Research of the Crohn’s and Colitis Foundation, presenting at Olink-sponsored workshops in Boston.

Over Nine Hundred Pediatric Crohns Patients in the RISK Cohort

Dr. Hurtado described a 13-year study of over 900 pediatric Crohn’s Disease patients followed up for 3 to 5 years post-diagnosis. They had biopsy samples from which they did RNA-Seq for gene expression, examined the patient microbiomes, and collected genotype information from each patient along with their therapeutic outcome.

These results, published in a 2017 Lancet paper related pediatric risk to treatment outcome by colon biopsy, and determined a gene-expression signature of genes associated with the extracellular matrix (ECM) forming an inflammatory signal.

This gene expression signature comprised of 78 genes, both to progression from B1 to B2, as well as from B2 to B3 and its penetrating complications. It had a high Negative Predictive Value (NPV) of 0.94, but a relatively low Positive Predictive Value (PPV) of 0.24 and an Area Under Receiver Operator Curve of 0.72 for early anti-TNF therapy.

The authors then used machine-learning with a research partner called LifeArc, affiliated with the Wellcome Trust to reduce the total number of genes in this inflammatory signal to 13 from the original 78, thereby improving the NPV value (0.99) as well as improving the AUROC value to 0.93. The PPV was still relatively low (0.33).

A new Olink screen for predictive and prognostic biomarkers

Dr. Hurtado then took the same RISK cohort samples and used all 14 available Target 96 panels (some 1100 protein biomarkers), identifying 14 proteins that had a very high predictive and prognostic value. As the patent was being filed along with the manuscript for publication, all he could say was that their circulating protein biomarker results were consistent with the ECM pathways that were observed to be upregulated in the biopsy tissue.

For disease prognosis, with 14 proteins they achieved a PPV of 0.83, an NPV of 0.67, and an AUROC of 0.84. For disease prediction, they identified three proteins that predicted response to anti-TNF therapy, with a PPV of 0.89, an NPV of 0.71, and an AUROC of 0.90.

As Olink has the capability to produce a 21-marker custom panel (called Olink Focus) the Crohn’s and Colitis Foundation wants to move forward with developing a custom panel to make an impact among so many who suffer from this debilitating illness.

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Kugathasan et al., 2017, Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study, The Lancet.

2947

Biomarker assays

~881 million

Protein data points generated

1049

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