During a recent Analytical Scientist roundtable symposium exploring New Frontiers in Non-Target Screening (available on demand here), a panel of experts was asked whether there is a meaningful distinction between untargeted and non-targeted screening.
Ian Wilson kicks off the discussion.
Ian Wilson: I was rather hoping that there was, but I think it’s largely a cultural difference. People have been using “untargeted screening” in metabolomics since the field began.
That said, I do think there are different varieties of what is called untargeted screening in metabolomics, and I think we would really benefit from being able to distinguish between them. What I would consider fully untargeted is where you don’t know what you’re looking for, and you don’t know what you’ve found. Then there’s the panel-based approach, where you know what you’re going to look for, but you don’t know how much it will have changed. For me, that would be non-targeted, while the fully untargeted version would be different.
But listening to the last presentation, it seems to me that many of the methodologies being used there are the same ones I’m using in mammalian metabolomics. That’s a pity, because I think it would be a really useful distinction.
Leon Barron: Yes, I agree with Ian. I think the historical context is, I suppose, “untargeted,” so I’m inclined to agree with his thinking.
Traditionally, for me at least – and again, this is probably just a cultural thing – the “non-target screening” moniker tends to refer to external contaminants rather than biomolecules. But I like what Ian said about it being hypothesis-generating. In environmental analysis, we don’t always know the source of the change. It’s quite complicated, so we don’t always have control over that.
But yes, I tend to agree with Ian. I think it’s a cultural thing, but I would like to see some differentiation between the two. What that is, I don’t know – but that’s my context.
Wilson: Well, perhaps we can start to define it. If we can agree that there is a difference, we can begin to define what that difference is. Whether the rest of the world would follow us, of course, is another matter.
Rob Plumb: I think there is a difference, Ian, if you think about a fully untargeted approach – typically using full-spectrum analysis, perhaps with an HRMS instrument in LC-MS.
In the approach you described, you have pre-selected components, but because you’re using an MRM-based approach, you also have very specific transitions. That gives you a form of specificity that, in some ways, removes the need to identify the component if it turns out to be one of interest.
Compared with a full-spectrum type of analysis, you probably also have much greater sensitivity because you’re using MRM and the specificity of MRM detection.
Sabrina Gensberger-Regal: To me, the two terms are quite similar, but in detail they mean slightly different things.
I would see “untargeted” as more of a discovery-driven approach, where we are looking for – and measuring – everything that is detectable, but still within a somewhat hypothesis-driven space. We can use databases, for example, and then match the data against those databases.
With “non-targeted screening,” I would think more of scanning for everything: a truly untargeted, or truly non-targeted, approach where I do not know what I am looking for, and where I do not have a predefined search space. Then we are dealing with chemical space, which is much, much larger outside the proteomics field.
Wilson: So we are using the same terms to mean exactly different things, which is going to be a real problem. Who is going to blink first: the proteomicists or the metabolomicists? As they don’t even talk to each other, it’s unlikely that the change will happen.
But we should discuss it, because if you believe that “untargeted” means something completely different from what I mean, then when we do start to have a conversation, we are going to confuse each other hugely.
Gensberger-Regal: I totally agree. And I think that is why it is so important to discuss this, and to be really clear about what we mean – and what we are referring to – when we use those terms.
Stefan Bieber: Well, to be honest, this discussion puts me in a rather difficult position, because I work for the Institute for Non-Target Screening, and I have just realized that, based on your definition, we mostly do untargeted analysis!
I’m not sure we need to go too deeply into this discussion, because what comes to my mind now is: if we differentiate between non-targeted and untargeted screening, where is the boundary with suspect screening?
What we often see in labs is that people say they are doing non-target screening, but what they are really doing is a scan experiment, followed by looking for things they already know are in there. I’m not sure there is such a clear boundary between suspect screening, non-target screening, and untargeted screening.
Wilson: I’m sure there isn’t a clear boundary, but I think, as Sabrina said, we need to get the conversation going so that we all realize we may be talking about completely different things.
At least if there is an acknowledgement that I mean one thing and you mean another – rather like the difference between American English and British English, where you can say the same thing but it doesn’t mean the same thing – then we can avoid some problems.
So let’s acknowledge that these terms can be used equivalently, or that in particular fields they may have a particular meaning. But we need to get that out there.
The exchange is taken from New Frontiers in Non-Target Screening: Roundtable Symposium, hosted by The Analytical Scientist in collaboration with the International Conference on Non-Target Screening. Watch the full webinar to hear experts from pharma and metabolomics, food science, environmental analysis, and materials and process monitoring discuss how NTS workflows are evolving.
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