Module - Whole System Molecular Medicine (SBI130)

STP

Aim of this module

It is becoming increasingly clear that diseases and disease processes are complex and involve many interactions within the genome, across metabolic pathways, and between the individual and the environment. Such considerations are important if the consequences of variations observed within an individual’s genome are to be effectively assessed. Rapid advancements in areas such as functional genomics and systems biology are now providing new insights into such processes. However, accessing these methodologies requires the use of forms of mathematics that have not been traditionally used within genetic medicine. This module will develop and strengthen the trainee’s mathematical and modelling skills, and introduce them to functional genomics and systems biology strategies and the ways in which they can be applied in medicine for improved patient care. This module will enable the trainee to gain experience of the process and application of the skill of literature searching and the use of bioinformatic resources within a clinical setting. This module will enable the trainee to develop and strengthen their mathematical and modelling skills and introduce them to functional genomics and systems biology strategies and the ways in which they can be applied in medicine for improved patient care within an ethical and governance framework.

Work-based learning outcomes

  1. Critically evaluate the literature and bioinformatic resources to identify biological pathways in which a gene(s) could participate.
  2. Critically evaluate the literature and bioinformatic resources to identify biological pathways that play a role in a specific disease process e.g. host/pathogen interactions.
  3. Develop pathways and network data to inform a service development, and enhance testing strategy for a specified patient population.

Work-based Competencies

Learning outcome Title Knowledge
1 1

Select a gene and perform a thorough literature search.
  • Robust and reproducible mechanisms for recording literature searches.

Bioinformatics pathway tools

  • Databases of metabolic networks (KEGG, Panther, etc.).
  • Databases of gene interactions (String, etc.).
  • Gene ontology and pathway analysis.
  • Strategies for determining whether a pathway is over-represented in a set of genes (Fisher exact t-test, methods based on gene lists).

Systems biology

  • Introduction to Systems Biology Markup Language (SBML).
  • Repositories of pathway models.
  • Determining model parameters from the literature.
  • Stability analysis of ordinary differential equations (ODE) models (Jacobians).
2 1

Identify bioinformatic resources for gene interactions and networks.
  • Robust and reproducible mechanisms for recording literature searches.

Bioinformatics pathway tools

  • Databases of metabolic networks (KEGG, Panther, etc.).
  • Databases of gene interactions (String, etc.).
  • Gene ontology and pathway analysis.
  • Strategies for determining whether a pathway is over-represented in a set of genes (Fisher exact t-test, methods based on gene lists).

Systems biology

  • Introduction to Systems Biology Markup Language (SBML).
  • Repositories of pathway models.
  • Determining model parameters from the literature.
  • Stability analysis of ordinary differential equations (ODE) models (Jacobians).
3 1

Identify biological pathways in which gene(s) operate.
  • Robust and reproducible mechanisms for recording literature searches.

Bioinformatics pathway tools

  • Databases of metabolic networks (KEGG, Panther, etc.).
  • Databases of gene interactions (String, etc.).
  • Gene ontology and pathway analysis.
  • Strategies for determining whether a pathway is over-represented in a set of genes (Fisher exact t-test, methods based on gene lists).

Systems biology

  • Introduction to Systems Biology Markup Language (SBML).
  • Repositories of pathway models.
  • Determining model parameters from the literature.
  • Stability analysis of ordinary differential equations (ODE) models (Jacobians).
4 1

Critically evaluate and integrate all information.
  • Robust and reproducible mechanisms for recording literature searches.

Bioinformatics pathway tools

  • Databases of metabolic networks (KEGG, Panther, etc.).
  • Databases of gene interactions (String, etc.).
  • Gene ontology and pathway analysis.
  • Strategies for determining whether a pathway is over-represented in a set of genes (Fisher exact t-test, methods based on gene lists).

Systems biology

  • Introduction to Systems Biology Markup Language (SBML).
  • Repositories of pathway models.
  • Determining model parameters from the literature.
  • Stability analysis of ordinary differential equations (ODE) models (Jacobians).
5 1

Produce a written summary of reference sequences and single-nucleotide polymorphisms (SNPs) within networks with phenotype information.
  • Robust and reproducible mechanisms for recording literature searches.

Bioinformatics pathway tools

  • Databases of metabolic networks (KEGG, Panther, etc.).
  • Databases of gene interactions (String, etc.).
  • Gene ontology and pathway analysis.
  • Strategies for determining whether a pathway is over-represented in a set of genes (Fisher exact t-test, methods based on gene lists).

Systems biology

  • Introduction to Systems Biology Markup Language (SBML).
  • Repositories of pathway models.
  • Determining model parameters from the literature.
  • Stability analysis of ordinary differential equations (ODE) models (Jacobians).
6 1

Identify and evaluate current state-of-the-art resources as appropriate.
  • Robust and reproducible mechanisms for recording literature searches.

Bioinformatics pathway tools

  • Databases of metabolic networks (KEGG, Panther, etc.).
  • Databases of gene interactions (String, etc.).
  • Gene ontology and pathway analysis.
  • Strategies for determining whether a pathway is over-represented in a set of genes (Fisher exact t-test, methods based on gene lists).

Systems biology

  • Introduction to Systems Biology Markup Language (SBML).
  • Repositories of pathway models.
  • Determining model parameters from the literature.
  • Stability analysis of ordinary differential equations (ODE) models (Jacobians).
7 2

Identify a disease area of interest following discussions with clinical teams, and perform a literature search around clinical phenotype, including any clinical databases.
  • Robust and reproducible mechanisms for recording literature searches.
  • Computational disease resources such as OMIM, GeneReviews.
  • Computational interactional resources for gene-gene, e.g. String.
  • Tools for identifying pathways that are over-represented in gene lists.
  • How to develop hypotheses around the potential phenotype of a mutation based on an analysis of the pathways and interactions in which it could participate.
  • How to evaluate the literature around systems biology pathway modelling to improve understanding of genetic disease processes.
  • How to determine the sensitivity of pathways to changes in gene function through the analysis of stability analyses.
  • How to apply systems biology strategies to improve identification of disease-specific mutations from NGS data.
  • Provision of strategic advice to clinical genetics service leaders in developing systems strategies for interpreting next generation and other large-scale sequencing data.
8 2

Interrogate a range of bioinformatic resources for disease pathway interactions.
  • Robust and reproducible mechanisms for recording literature searches.
  • Computational disease resources such as OMIM, GeneReviews.
  • Computational interactional resources for gene-gene, e.g. String.
  • Tools for identifying pathways that are over-represented in gene lists.
  • How to develop hypotheses around the potential phenotype of a mutation based on an analysis of the pathways and interactions in which it could participate.
  • How to evaluate the literature around systems biology pathway modelling to improve understanding of genetic disease processes.
  • How to determine the sensitivity of pathways to changes in gene function through the analysis of stability analyses.
  • How to apply systems biology strategies to improve identification of disease-specific mutations from NGS data.
  • Provision of strategic advice to clinical genetics service leaders in developing systems strategies for interpreting next generation and other large-scale sequencing data.
9 2

Critically evaluate and integrate all information.
  • Robust and reproducible mechanisms for recording literature searches.
  • Computational disease resources such as OMIM, GeneReviews.
  • Computational interactional resources for gene-gene, e.g. String.
  • Tools for identifying pathways that are over-represented in gene lists.
  • How to develop hypotheses around the potential phenotype of a mutation based on an analysis of the pathways and interactions in which it could participate.
  • How to evaluate the literature around systems biology pathway modelling to improve understanding of genetic disease processes.
  • How to determine the sensitivity of pathways to changes in gene function through the analysis of stability analyses.
  • How to apply systems biology strategies to improve identification of disease-specific mutations from NGS data.
  • Provision of strategic advice to clinical genetics service leaders in developing systems strategies for interpreting next generation and other large-scale sequencing data.
10 2

Produce a written summary of the biological pathways with phenotypic information.
  • Robust and reproducible mechanisms for recording literature searches.
  • Computational disease resources such as OMIM, GeneReviews.
  • Computational interactional resources for gene-gene, e.g. String.
  • Tools for identifying pathways that are over-represented in gene lists.
  • How to develop hypotheses around the potential phenotype of a mutation based on an analysis of the pathways and interactions in which it could participate.
  • How to evaluate the literature around systems biology pathway modelling to improve understanding of genetic disease processes.
  • How to determine the sensitivity of pathways to changes in gene function through the analysis of stability analyses.
  • How to apply systems biology strategies to improve identification of disease-specific mutations from NGS data.
  • Provision of strategic advice to clinical genetics service leaders in developing systems strategies for interpreting next generation and other large-scale sequencing data.
11 2

Identify and evaluate current state-of-the-art resources as appropriate.
  • Robust and reproducible mechanisms for recording literature searches.
  • Computational disease resources such as OMIM, GeneReviews.
  • Computational interactional resources for gene-gene, e.g. String.
  • Tools for identifying pathways that are over-represented in gene lists.
  • How to develop hypotheses around the potential phenotype of a mutation based on an analysis of the pathways and interactions in which it could participate.
  • How to evaluate the literature around systems biology pathway modelling to improve understanding of genetic disease processes.
  • How to determine the sensitivity of pathways to changes in gene function through the analysis of stability analyses.
  • How to apply systems biology strategies to improve identification of disease-specific mutations from NGS data.
  • Provision of strategic advice to clinical genetics service leaders in developing systems strategies for interpreting next generation and other large-scale sequencing data.
12 3

Use network strategies from learning outcomes 1 and 2 to develop an enhanced testing strategy.
  • Gene Dossier process.
  • Ethical and governance frameworks.
13 3

Determine if pathway-based gene testing is appropriate.
  • Gene Dossier process.
  • Ethical and governance frameworks.
14 3

Document the analysis process, justify the recommendation and proposed gene panel (if recommended).
  • Gene Dossier process.
  • Ethical and governance frameworks.

Work-based assessment

Complete 2 Case-Based Discussion(s)
Complete 2 of the following DOPS and/or OCEs
Type Title
DOPS Generate a list of papers related to a specific disorder to form the basis of a systematic review Identify the biological pathway in which a specific gene operates using available databases
DOPS Following a SOP run the NGS data for a batch of samples through an analysis pipeline and output a list of filtered variants for each sample.
DOPS Evaluate the quality of a NGS run using suitable quality control tools e.g. FASTQC
DOPS Run checks on the data processed and trigger appropriate actions before sending to Clinical Scientists
OCE Discuss a specific clinical condition with relevant clinical team
OCE Present results of an NGS based analysis to an MDT meeting