Are you looking for a needle in a haystack? Then imagine looking for it without knowing what a needle looks like. The genome knowledge of today is quite far from being as unstructured as the haystack in the analogy, yet, despite several big leaps, we haven’t done much of the journey in understanding the function and contribution of the genome in health and disease.

With the avenue of high throughput measurement technologies such as next generation sequencing the hypothesis-driven investigative research approach has been complemented with data driven approaches. Let the data talk! If you find something exceptional in one haystack that is absent from the other,  it will certainly be worth further attention, whether it is the needle you went out searching for or not. In scientific terms, though, let’s rather talk about cohorts than haystacks.

Cohort analysis involves studying groups of objects, such as individuals, who share, or differ over some defined characteristics with the purpose to find some underlying cause – the needle. High throughput sequencing provides one analogy of the haystack. This is a typical premise-based scientific research approach. Also in the realm of clinical genetics, cohort analysis can be very illuminating. By scrutinizing the occurrence of genomic variants and other epigenetic features in cohorts, one can investigate how they influence the risk, onset and progression of diseases, the effectiveness of treatments, or the emergence of potential side effects.

This case study delves into the role of cohort analysis in clinical genetics research, highlighting its methodologies, challenges, and breakthroughs. By examining the whole exome and whole genome sequencing -powered studies, the readers will gain an appreciation of how cohort-based approaches can shed light on the intricate relationship between our genes and our health.

Folkhälsan Research Challenge

Folkhälsan is an organisation in Finland that works for better health and quality of life. Our operations in Finland and on the Åland Islands include daycare centres, support for young people, education, services for the elderly and people with disabilities, as well as a world-class research centre. Folkhälsan research centre works in close collaboration with Helsinki University Hospital. Researchers typically also work in clinical practice and teach in the Medical School. 

There are two research groups at Folkhälsan that leverage genomic information in their studies. A group led by Marco Savarese is looking for novel variants, genes, and mechanisms causing human skeletal muscle diseases. 

Second group, led by ophthalmologist Joni Turunen, is researching genetic eye diseases. In collaboration with Helsinki University Hospital the focus of the group is a detailed clinical phenotypic characterization of genetic eye diseases, gene discovery, functional testing of variants in laboratory assays, and ultimately development treatments. The group utilises up-to-date genetics methods including exome, whole-genome, and long-read sequencing.

Clinical Research using a Diagnostics Tool

Both groups are analysing genetic variants using omnomicsNGS, a CE-IVD marked tool for tertiary analysis (variant annotation, curation, filtering and interpretation) of genomic data from patient samples. While the software tool was initially developed for clinical diagnostics and is used for that purpose by multiple university hospitals and private clinical laboratories on 4 continents a need emerged to look at data from multiple samples simultaneously instead of just one at a time.

The cohort analysis functionality was developed into omnomicsNGS on top of the systems variant knowledge base documenting all sample variants. The team at Folkhälsan helped in elaborating some key features of the module. The cohort analysis functionality applies filtering and prioritization of variants in a way akin to what is done in single sample diagnostics. As a result it becomes possible to organize variants based on their features prior to asking qualitative or quantitative questions concerning correlation, association and causation.

After using the system for several months for clinical research, researchers at Folkhälsan can share their experiences. Marco’s team comments that “we finally have the tool we were looking for. We can browse our cohort and retrieve variants in a specific gene of interest in a few seconds. This allows us to periodically re-check our results in search for ´new´ findings in old data”. 

Joni continues by saying that “In genetic research with current sequencing technology, you gather an enormous amount of data relatively easily. We acquired the omnomicsNGS to speed up the guest for often single causative gene variants from hundreds of thousands of genetic variants. We have utilized the platform in the situations of familial diseases, whole genomic data and in the cohort analysis

Based on the feedback from Folkhälsan, Euformatics continues to refine the clinical research capabilities in the Genomics Hub tools. 

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