Uncertainty in genetic medicine – what’s inevitable, what’s avoidable?

question-mark-1119854_640The damaging impacts of uncertainty have been much in the news following the global turmoil and incertitude precipitated by Brexit.

But uncertainty is not always damaging. And, it is an essential, inescapable part of living that most of us are very thankful for. We do not want our lives to be preordained to follow a certain path.

So the word ‘uncertainty’ is used in different contexts to cover immutable and positive situations as well as avertible and negative ones.

Both contexts are highly relevant to genetic medicine.

Two types of uncertainty are pervasive in genetic medicine today: uncertainty of knowledge and uncertainty of process. The former is inevitable and drives progress; the latter is avoidable and hinders progress. Recognising and effectively communicating these different sorts of uncertainty is crucial to making genetic medicine work.


Uncertainty of knowledge

Genetic knowledge, and its use in medicine, is advancing at terrific speed. Inevitably this means some things we believed and did yesterday are different, sometimes dramatically so, from what we know and do today. One of the few certainties we can rely on is that many things we believe and do today will alter, because of new knowledge, tomorrow. This is what innovation and progress look like in the real world. It is fantastic and should be warmly embraced.

Two types of uncertainty are pervasive in genetic medicine: uncertainty of knowledge and uncertainty of process. The former is inevitable and drives progress; the latter is avoidable and hinders progress.

For example, in our last post we described how new knowledge had allowed a variant in the cystic fibrosis gene to be reclassified as not causing the disease, with huge benefits for the family. Over the next few years we will see many so-called ‘variants of uncertain significance’ become reclassifiable through new knowledge of variant spectra and frequency, together with new analytical and experimental methods for their evaluation.

Sometimes the original classification is described as ‘an error’, fortifying an emerging blame and compensation culture, as evidenced by recent lawsuits. As well as being an inappropriate description of progress, this mindset is generating fear and self-defeating caution in genetic medicine. We must act now to stop it. Instead of viewing new recommendations as evidence that we were previously wrong, patients and doctors should be aware, pleased and grateful, that new advice about the implications of genetic information, at both the general and individual level, is a likely, welcome outcome of ongoing progress.

Personally I have not found communication of updated knowledge overly difficult. People are generally understanding and accepting of a situation in which the available knowledge meant they were told one thing, but new knowledge means that they are being told something different. Typically, only if they were unaware the information and recommendations could possibly change have people been (initially) less understanding.


Uncertainty of process

We should all aspire to be clear and transparent about the processes we are using in genetic medicine, particularly where we may need to update recommendations. As these are the very processes that are most challenging to define, we must give diligent attention to providing the requisite clarity.

In reality, many aspects of genetic medicine are not being well communicated, often because they have not been well defined. It’s nearly impossible to effectively communicate what you will do, if you have not decided!

To take again the example of ‘variants of uncertain significance’, the process for the ongoing management of such variants needs to be crystal clear between the lab doing the test, the doctor ordering it and the patient being tested. We will return to how this can be achieved in future posts – it is a focus of TGMI activity – but transparency on how updated variant information will be handled must be included.

The field is still working out the minimal and optimal standards that should be used and systematic collation and curation of variant interpretation is in its infancy. However, this does not stop labs and doctors from stating what they are doing, nor does it remove their responsibility to do so.

Some labs only review a variant’s classification on request whereas others routinely undertake periodic review of a variant’s classification. Either could be construed as a reasonable approach; ongoing review of variants is currently an onerous and expensive activity. But it is vital everyone involved knows which system is being used. This is because updated variant information is unlikely to be fed back unless requested in the first system, but is likely to be fed back automatically in the second system.

Importantly, transparent communications reduce the feelings of grievance and distress that can be experienced if people have erroneous assumptions about a process, e.g. if they had assumed variant information would not change or that they would be automatically informed if there was a change. It should not be underestimated how many disputes, tears and lawsuits are caused by this entirely avoidable type of uncertainty.


What is the TGMI doing?

The TGMI is addressing both types of uncertainty in relation to variants. We aim to improve the knowledge base underlying variant interpretation so that more robust standardised processes for their management can be defined.

Please contact us or comment below if uncertainty in genetic medicine has had an impact on you, either as a researcher, practitioner or patient.