Artificial intelligence knocking on the wall!

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Applications of artificial intelligence (AI) are becoming more and more common in daily life, and medicine. It’s public knowledge that AI algorithms are much better at detecting a pneumonia on a chest X-ray than radiologists of flesh, blood and … insomnia. A similar problem arises when judging whether MS lesions on a brain scan have increased in volume over time. (Un)fortunately, lesions never double in volume. Radiologists need to pick up volumetric increases of 1 or 2 mL and it’s unrealistic to expect that this will be done flawless. Hence, a clear window for AI algorithms to improve healthcare and patient outcomes. The AI algorithms recognise patterns in data, and create their own logic. To gain useful AI insights and predictions, it is key that the models are trained using extensive amounts of input data, far beyond what any brain could handle.  

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A new study applied AI on brain MRI data to categorise pwMS in different subtypes. They used input data from 6322 pwMS to define MRI-based subtypes on an independent cohort of 3068 pwMS for validation. Scans were processed to quantify volume loss and tissue damage in different brain regions and MS lesion volume. These data were used to train and validate the AI algorithm, and three MRI patterns became apparent: a cortex-led, a white matter-led, and a lesion-led subtype. The cortex-led subtype with conspicuous damage in the outer layer of the brain was most frequent. People with the lesion-led subtype had the most aggressive disease course: more contrast-enhancing lesions, more relapses and a higher risk of accumulating disability over time. Importantly, people with the lesion-led MS subtype showed a positive treatment response whereas people with the cortex-led subtype did not respond well to MS treatments.  

PwMS are wondering now: which MRI subtype am I? 

Very good question. However, I’m not able to give you an answer. These AI algorithms are not battle-zone ready. This means that we cannot apply them in clinical practice (yet). The current algorithm was trained with MRI data from the ‘perfect’ world: pharma-led clinical trials. In reality, there is much more technical noise and more variable intervals between first symptoms-first scan, and first scan-second scan, etc. However, this is probably the least unsurmountable problem as logistics are – as always- only a temporary distraction. 

Therefore, the better question would be: does it matter which subtype am I?

Maybe. The AI algorithm clearly showed that response to immunotherapy is largely lesion-dependent. This is very interesting but also largely in line with our current – admittedly simplistic – non-AI-based clinical practice when it comes to treating pwMS. We select pwMS for treatments based on the presence or absence of new/enhancing lesions on their latest brain scan. Is it excluded that cortex-led pwMS develop new lesions? No, not at all. Would anyone refuse treatment in a patient with a cortex-led subtype who now has a new lesion? No. Because essentially every pwMS is a bit over everything. Everyone is a bit of lesion-led, a bit of cortex-led and a bit of white matter-led. Although you match better with one of these subtypes, you are unlikely to be a perfect match. The results in the paper clearly show that the lesion-led and cortex-led subtype are two extremes of a spectrum, with the white-matter led subtype sitting right in the middle. This means that annual relapse rate is higher in the lesion-led > white-matter-led > cortex-led subtype. Therapeutic response followed the same pattern of gradual decay. This clearly implies that the AI algorithm categorised an MRI spectrum in three boxes; like splitting a circle into three. 

Nonetheless, I am pretty convinced that these AI boxes are more accurate than the clinical boxes neurologists like to use (relapsing-remitting vs.progressive). Clinical phenotyping is outdated, and the only thing that probably matters when starting MS treatments is whether you have ongoing/active inflammation or not. Luckily, pharmacological walls are progressively breaking down with the advent of Ocrevus for primary progressive MS and siponimod for secondary progressive MS. And if AI algorithms are gonna knock on this wall, we are happy to join. Knock Knock!

Twitter: @SmetsIde

Disclaimer: Please note that the opinions expressed here are those of Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Nat Commun 2021 Apr 6;12(1):2078. doi: 10.1038/s41467-021-22265-2.

Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data

Arman Eshaghi 1 2, Alexandra L Young 3 4, Peter A Wijeratne 3, Ferran Prados 5 3 6, Douglas L Arnold 7, Sridar Narayanan 7, Charles R G Guttmann 8, Frederik Barkhof 5 3 9 10, Daniel C Alexander 3, Alan J Thompson 5, Declan Chard # 5 11, Olga Ciccarelli # 5 11

  • PMID: 33824310
  • PMCID: PMC8024377
  • DOI: 10.1038/s41467-021-22265-2

Abstract

Multiple sclerosis (MS) can be divided into four phenotypes based on clinical evolution. The pathophysiological boundaries of these phenotypes are unclear, limiting treatment stratification. Machine learning can identify groups with similar features using multidimensional data. Here, to classify MS subtypes based on pathological features, we apply unsupervised machine learning to brain MRI scans acquired in previously published studies. We use a training dataset from 6322 MS patients to define MRI-based subtypes and an independent cohort of 3068 patients for validation. Based on the earliest abnormalities, we define MS subtypes as cortex-led, normal-appearing white matter-led, and lesion-led. People with the lesion-led subtype have the highest risk of confirmed disability progression (CDP) and the highest relapse rate. People with the lesion-led MS subtype show positive treatment response in selected clinical trials. Our findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to define groups of patients in interventional trials.

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Ide Smets

9 comments

  • I made the same point couple of months ago and was ridiculed for being tin foil wearing nut. Inspite of working in this field. Apparently my experience and knowledge wasn’t enough to convince researchers we are living through the next age defining moment in history. From stone age, bronze age, iron age and now AI age. Days of human intelligence as top dog are numbered.

    • HAL 9000 : Look Dave, I can see you’re really upset about this. I honestly think you ought to sit down calmly, take a stress pill, and think things over. I know I’ve made some very poor decisions recently, but I can give you my complete assurance that my work will be back to normal. I’ve still got the greatest enthusiasm and confidence in the mission. And I want to help you.😊

      When you say lesion-led MS type is more responsive to therapy I assume this is due to active breakdown in the BBB and the ability of the drug to penetrate at the site. Once again delivery of the drug to the site is critical.

      • I think this is because current MS treatments are immune suppressive, and thus target inflammation such as represented by MS lesions in the brain. We do not have neuroprotective agents in MS yet, and thus cannot undo brain volume loss or atrophy such as seen in the cortex-led subtype.

  • Ide,

    Thanks for your post.

    How do the three subtypes (above) fit with Prof G’s proposal that MS is one disease?

    A few years after I was diagnosed the US National MS Society funded the Promise 2010 programme. One element of this was the MS Lesion Project: “Claudia F. Lucchinetti, MD, with collaborators in the U.S., Germany and Austria, launched the most extensive attempt ever to map and understand the meaning of MS damage in the brain. They amassed an unprecedented collection of tissue samples from more than 1,000 people with MS, obtained from brain biopsies (a rare procedure) or autopsies. By identifying four distinct kinds of lesion patterns…..”. Is this work now defunct given the three sub-types identified in the research above?

    Final question (sorry). Can MS still be viewed as a disease where the immune system attacks myelin? It now appears to be a global disease of the CNS and myelin is destroyed as with neurons, axons etc ie myelin isn’t a specific target?

    • I also think it’s one disease which is divided by the AI algorithm in three ‘artificial’ subtypes. Nonetheless, these subtypes are probably better at categorising MS than the clinical subtypes such as relapsing or progressive MS.

      This paper was based on MRI data, and when these data were put into the AI algorithm, it resulted into three subtypes. When you put other data in, you get other information out. Likely, if pathology data would be the input, the number of subtypes would be different.

      Yes, MS can still be seen as a disease in which the immune system attacks myelin, and secondary to this inflammatory attack there is more widespread brain damage.

    • Good point, I’ve always wondered this, myelin outside of the nervous system is unaffected, so is it the brains own immune system causing the damage and/or recruiting the peripheral immune system to attack.

      Or is it’s an toxin and energy issue in the brain, causing the progressive side and brain atrophy.

      Or maybe starts in the gut, chemical signals, bacteria making its way to the brain and passing the bbb then being attacked

      Who knows, however If super computers such as quantum computers become used in medicine in time to come, it will possibly solve this.

      Computers have already helped people with MS I.e the internet and mri. This is just another piece to the puzzle.

    • MS shouldn’t be categorized as RR/PP/SP. However, MS is clearly not 1 disease to me, as people who failed on high-efficacy drugs can have some response on lower efficacy drugs with a different immune pathway/moa. The way our immune system malfunctions are different, therefore treatments should be different. Sadly we don’t have enough knowledge yet to create accurate subtypes as we don’t have biomarkers to differentiate subtypes.

      • Also, history suggests MS is not one disease. NMOSD, including MOGAD, used to be considered kinds of MS.

        Furthermore, the MS diagnosis is largely a diagnosis of elimination.

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