metadata driven

Technology should not aim to replace humans, rather amplify human capabilities.

Doug Engelbart, Stanford Research Institute, 1968

An interesting topic arose in the latest Veramed Stories Podcast Paraphrased as:

When I first heard about (clinical trial) automation and AI, I thought “will it put us all out of a job?”

Veramed Stories Podcast Episode 007

A great question which speaks to real concerns and forces us to examine why we are automating in the first place, and what we hope to achieve.

Increasing employment rates

The World Economic Forum estimates that by 2025, technology will create at least 12 million more jobs than it destroys, a sign that in the long run, automation will be a net positive for society

Harvard Business Review

Clearly the utopian life of leisure is not here, and shows no signs of being around the corner!

So, if IT automation has resulted in more people working, not less, then what is the point? why are we automating anything?

Augmented human intellect

The foundations of the ‘IT revolution’ can be found in Doug Engelbart’s 1958 paper Augmented Human Intellect: A conceptual framework

By “augmenting human intellect” we mean… more rapid comprehension, better comprehension, the possibility of gaining useful degree of comprehension in situation that previously was too complex, speedier solutions, better solutions, and the possibility of finding solutions to problems that before seemed insoluble.

Introduction to Augmented Human Intellect: A Conceptual Framework

The goal is to optimize comprehension, not to reduce or eliminate work.

Automation is one of the tools that we use to improve comprehension – it allows us to crunch more data, more quickly, and to visualise it more easily.. all of which helps reduce “time to insight”.

Automation transforms jobs

So, to address the original question – will automation replace your job? No. However is will certainly change your job.

The tools and processes that we use to design clinical trails, specify what data to collect, how to analyse the data and report on trials will all change.

The goal (of automation) is not (to employ) less people; The goal is better comprehension, more quickly.

Behold, the people is one, and they have all one language… and now nothing will be restrained from them, which they have imagined to do.

Genesis 11:6

A compelling vision

Clinical Trial analysis and reporting is changing, driven by a vision of end-to-end automation which aims to substantially improve efficiency, consistency, and re-usability across the clinical research data lifecycle.

Conferences are a buzz with debate on the best languages to use to implement this future vision – will SAS prevail? or open-source languages like R or Python?..

Addressing the challenge of automation by talking about programming languages is like looking at the Moon with a microscope!

Programmer Proverb

This article aims to look at the heavens using a telescope!.. OK, enough with the analogies!

Let’s start by trying to understand what exactly the challenge is with automation?

Trouble in paradise

Lets consider a typical automation project:

First, you build a proof-of-concept – maybe an R-Shiny front-end onto a SAS backend that re-uses macros that you’ve been using for years. Everything looks good, ‘click-a-button’ demos, great powerpoints, and everyone is excited… so onto the next stage…

Next is a pilot project – you need something more robust (did someone mention validation??).. Build a web interface in Python, put the metadata in a (graph?) database with the remnants of the PoC (which has now been tested) driving the SAS backend.

Perfect! Now you can see the benefits of “substantially improved efficiency, consistency, and re-usability”.. Can’t you?

What do you mean no? Why not?

Well, because there still seems to be a lot of manual work managing all that metadata.

The problem is that while we no longer have to manually create and configure a suite of programs, now instead, we have to manually create and configure all the metadata that drives the automation.

So, the challenge of automation is actually the challenge of how to efficiently manage metadata.

The tower of Babel

So, lets now examine the source of this inefficiency. We can trace it back to a couple of key assumptions:

1. A clinical trial involves many specialist roles – Investigators, Clinicians, Regulators, Data Managers, Statisticians, etc. Each with their own definitions and terminology – their own domain-language. The assumption that a single common data model can fit all these specialist sub-domains results in a data model that is unwieldy, hard to use and even harder to change.
2. The assumption that metadata must be stored in a central metadata repository (MDR) leads to a ‘database-centric architecture’ which is problematic in its own right, and also has increased cost of ownership (e.g. managing and maintaining the database server) – not to mention the ubiquitous form-based user interface that needs an endless series of click-and-wait manual steps for every task

These assumptions lead to a ‘tower of babel’ scenario where we have a common data model that is stretched in every direction trying to support every nuance of every domain-expert, and is stored in a central database which becomes increasingly inefficient to use and manage as it gets wrapped in IT processes and change requests.

What we need is an ‘de-centralised’ approach that does not have a single common model in a central repository

Confound their language

To explore what such a ‘de-centralised’ approach might look like, let’s walk through an example using the BRIDG model

The goal of the BRIDG Project is to produce a shared view of the semantics of a common domain-of-interest, specifically the domain of basic, pre-clinical, clinical, and translational research and its associated regulatory artefacts.

BRIDG Model website.
https://bridgmodel.nci.nih.gov/

The diagram below shows the BRIDG model in its full glory. If this one diagram does not communicate the complexity of a single domain model then nothing will!

To be fair, BRIDG make it clear that this comprehensive view is published to check model integrity, and users are recommended to use the sub-domain views to understand the model.

The fact that BRIDG recommends sub-domain views confirms the complexity of a common model, but also identifies a solution – simply split the common model into parts!

The annotations in the diagram above are simply drawn onto the image – they are not part of the model, do not describe the relationship between sub-domains, and are not machine readable.

The BRIDG model is written in Unified Modelling Language (UML), a general-purpose modelling language intended to provide a standard way to visualize the design of a software system.

What we need is a “meta” language that sits “above” UML, to describe component parts and relationships between these parts.

Positive space

More specifically, we want to use this “meta language” to:

• Model different sub-domains of the clinical trials lifecycle that have specific terminology and definitions used by domain expert working within that sub-domain, because e.g. Statistician’s speak a different language than Investigators, or Data Managers, etc.
• De-couple sub-domains and describe relationships between them and how they are shared and translated. For example both the Experimental and the Statistical Analysis sub-domains have the concept of an unscheduled visit, but each treats them differently, however we still want to link and translate between the two.

Great – so now we know what we want to do with our “meta language”.. but what is it?…

A pattern language

A pattern language is an organized and coherent set of patterns, each of which describes a problem and the core of a solution that can be used in many ways within a specific field of expertise.

https://en.wikipedia.org/wiki/Pattern_language

The term “pattern language” was coined by architect Christopher Alexander in his 1977 book A Pattern Language.

Although the original concept came from building architecture and urban planning, pattern languages have since been used in many other disciplines – and since the 1990s for software design patterns.

One such software pattern language is Domain-Driven Design (DDD), a term coined by Eric Evans in 2003 in his book of the same name.

Domain-Driven Design

Domain-driven Design is a software design approach focusing on modelling software to match a domain according to input from that domain’s experts.

https://en.wikipedia.org/wiki/Domain-driven_design

Well, that sounds promising! Let’s see if we can apply Domain-Driven Design to the BRIDG model…

DDD uses context maps to describe how a domain is divided into parts and the relationships between those parts.

Consider the BRIDG context map below, which was generated from a description written in the Context Mapper language. Notice how this resembles the informal annotations on the UML diagram above.

However, this context map is fundamentally different from the annotated UML diagram above, because:

• This context map is generated using a domain-specific language (DSL), which means that the pattern language is an actual ‘computer language’ that can be used in programming editors like VS Code or Eclipse, etc. with syntax highlighting, code-completion, etc.
• Not only can the DSL be used to generate diagrams, it can also be transformed into other models – for example into microservice contracts which in turn can be used to generate code.

So there we have it! A pattern language that allows us to pull down the Tower of Babel.

• We can create models of the clinical trials domain split into component parts, and model those parts independently while managing the interfaces between them. So, we don’t need a single common data model.
• We can treat metadata like program files – stored in text files that are ‘linked’ together when they are ‘run’. So, we do not need a central database to store metadata.
• Metadata is machine-readable and can be transformed into different metadata files, diagrams, or program code that processes clinical data. So, we can automate end-to-end

Summary

We started off by looking for a way to deliver on the vision of end-to-end automation and achieve the benefits of substantially improve efficiency, consistency, and re-usability across the clinical research data lifecycle.

The assumption that we need a single common data model stored in a central repository leads to inefficiencies which negate the benefits of automation.

Pattern languages are commonly used in software engineering for reusable solutions to commonly occurring problems, and we walked through an example by applying Domain-Driven Design to the BRIDG model.

Using a domain-specific language (DSL), we are able to split the common data model into parts, and store each part as machine-readable metadata in text files to generate code.

This approach streamlines metadata management because we can leverage source-code processes and tools to manage metadata – syntax checking, version control, unit testing, CI/CD, etc… and not a web-form in sight!

Stay tuned for more examples and demos which are in the pipeline.. in the meantime here is some background reading:

References

• Domain Driven Design Quickly.
• Domain-Specific Languages Guide.
• Context Mapper Language
• Language Orientated Programming: The Next Paradigm.

Why is it so hard to automate the analysis of a regulated clinical trial?

Sure, you might be able to setup an EDC in the blink of an eye, but lets be honest – it still takes a team of people years of effort to analyse the results and produce the tables, figures and listings (TFL) that go into the Clinical Study Report.

You’ve done a proof-of-concept or two, maybe piloted automation of SDTM datasets, and have bought into the end-to-end automation vision.. but how do you get there from here? And why does it seem so hard?

Automation is the tip of the iceberg

The first thing to recognize is that automation is not standalone. To achieve end-to-end automation in a production environment means that all the necessary metadata is available at each step of the process; the key people have the tools and skills to curate and manage that metadata; and they need a robust and validated software platform that meets regulatory submission and GCP quality requirements.

Ok, so lets looks as each of the areas than are needed to support successful automation of analysis results.

Don’t build a horse-less carriage

Before Henry Ford started building the Model T using a production line, cars were build in the same was as horse-drawn carriages has been – by a small team of highly skilled people that worked on the product from beginning to end.

Sound familiar?

Change and disruption caused by the introduction of automation is well understood in manufacturing, however it is a new phenomenon in knowledge-based industries.

Don’t re-invent the wheel either

The software industry pioneered Model-Driven Development (MDD) twenty years ago, and there now exist ISO Standards for Model-Driven Architecture, methodologies and tools that have been used successfully in regulated, safety-critical industries such as avionics, space, energy, etc.

Adoption of Model Driven Development can be mapped out using the Capability Maturity Model (see: MDD Maturity Model)

Level	Maturity	Description
1	Ad-Hoc	Analyses are not model-driven
2	Basic	Basic use of models in organization.
3	Initial	The organization starts developing systems more according to model model-driven approach.
4	Integrated	Models at different abstraction levels are built and they are fully integrated within a comprehensive modelling framework
5	Ultimate	The role of coding will disappear and the transformations between models are automated.

So, while most organizations will be starting at level 1 (i.e. Analyses are created manually), the question is: What level of adoptions do you aspire to? and over what timescale?

Then you can plan how to transition to level 2 – i.e. basic metadata-driven automation running end-to-end through the analysis.

Model-driven architecture

Possibly the clearest way of describing the architecture required to support a fully automated analysis using a Four layered metamodel architecture:

Layer	Contents	Description
M3	Meta-metamodel	Metadata standards, e.g. W3C Semantic Web, XML, UML, ISO11179, etc.
M2	Metamodel	Clinical Standards, e.g. CDISC, MEdDRA, SNOMED, etc.
M1	Model	Trial-specific Metadata
M0	Data	Clinical, Rando, Labs Data, etc.

Each level of the Metadata Architecture requires its own set of tools and processes, and people with the skillset to be able to work at the relevant level of abstraction.

Taking the first step

While a full-blown end-to-end level-5 CMM Ultimate Meta-Model Architecture may remain a powerpoint vision, there is more than enough work involved in getting from level-1 to level-2.

A full list is clearly out of the scope of this blog post(!), however, some things to consider include:

• Statisticians will need to be able to create a SAP in a machine-readable format. What tools will they use? who will train and support them?
• Programmers will need to be able to work with technologies such as XML, RDF,/OWL, Relational and Graph databases.. and probably using languages other than SAS
• How is study-specific data handled? How do you work around partial and dirty data?
• Software infrastructure to support version control, continuous integration/deployment, metadata repositories
• How will validation be done without ‘mainline’ and ‘qc’ programs?
• Business processes will be needed to support a software development and DevOps
• How will Industry Standards (e.g. CDISC) be managed? What about Corporate and Study/Drug/Disease-Specific standards? What happens when a new version of a standard is issued?

None of these issues are insurmountable, but equally they add up to more than an quick fix.

Summary

The promise of end-to-end automated analysis of clinical trials is not just that it will be faster and easier, but also the new and innovative applications that will be unlocked (CMM Level 3 and beyond).

Key points to consider in planning an automation strategy are:

• Automation requires metadata, and that means new tools, skills and business processes.
• This is mostly a solved problem, but will require learning lessons from other industries
• While implementing end-to-end automation requires work, ultimately is means that you spend less time on grunt-work and more time on activities that add value and ultimately help patients!