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    Neurodegenerative disease can progress in newly identified patterns

    Neurodegenerative diseases — like amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), Alzheimer’s, and Parkinson’s — are complicated, chronic ailments that can present with a variety of symptoms, worsen at different rates, and have many underlying genetic and environmental causes, some of which are unknown. ALS, in particular, affects voluntary muscle movement and is always fatal, but while most people survive for only a few years after diagnosis, others live with the disease for decades. Manifestations of ALS can also vary significantly; often slower disease development correlates with onset in the limbs and affecting fine motor skills, while the more serious, bulbar ALS impacts swallowing, speaking, breathing, and mobility. Therefore, understanding the progression of diseases like ALS is critical to enrollment in clinical trials, analysis of potential interventions, and discovery of root causes.

    However, assessing disease evolution is far from straightforward. Current clinical studies typically assume that health declines on a downward linear trajectory on a symptom rating scale, and use these linear models to evaluate whether drugs are slowing disease progression. However, data indicate that ALS often follows nonlinear trajectories, with periods where symptoms are stable alternating with periods when they are rapidly changing. Since data can be sparse, and health assessments often rely on subjective rating metrics measured at uneven time intervals, comparisons across patient populations are difficult. These heterogenous data and progression, in turn, complicate analyses of invention effectiveness and potentially mask disease origin.

    Now, a new machine-learning method developed by researchers from MIT, IBM Research, and elsewhere aims to better characterize ALS disease progression patterns to inform clinical trial design.

    “There are groups of individuals that share progression patterns. For example, some seem to have really fast-progressing ALS and others that have slow-progressing ALS that varies over time,” says Divya Ramamoorthy PhD ’22, a research specialist at MIT and lead author of a new paper on the work that was published this month in Nature Computational Science. “The question we were asking is: can we use machine learning to identify if, and to what extent, those types of consistent patterns across individuals exist?”

    Their technique, indeed, identified discrete and robust clinical patterns in ALS progression, many of which are non-linear. Further, these disease progression subtypes were consistent across patient populations and disease metrics. The team additionally found that their method can be applied to Alzheimer’s and Parkinson’s diseases as well.

    Joining Ramamoorthy on the paper are MIT-IBM Watson AI Lab members Ernest Fraenkel, a professor in the MIT Department of Biological Engineering; Research Scientist Soumya Ghosh of IBM Research; and Principal Research Scientist Kenney Ng, also of IBM Research. Additional authors include Kristen Severson PhD ’18, a senior researcher at Microsoft Research and former member of the Watson Lab and of IBM Research; Karen Sachs PhD ’06 of Next Generation Analytics; a team of researchers with Answer ALS; Jonathan D. Glass and Christina N. Fournier of the Emory University School of Medicine; the Pooled Resource Open-Access ALS Clinical Trials Consortium; ALS/MND Natural History Consortium; Todd M. Herrington of Massachusetts General Hospital (MGH) and Harvard Medical School; and James D. Berry of MGH.

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    MIT Professor Ernest Fraenkel describes early stages of his research looking at root causes of amyotrophic lateral sclerosis (ALS).

    Reshaping health decline

    After consulting with clinicians, the team of machine learning researchers and neurologists let the data speak for itself. They designed an unsupervised machine-learning model that employed two methods: Gaussian process regression and Dirichlet process clustering. These inferred the health trajectories directly from patient data and automatically grouped similar trajectories together without prescribing the number of clusters or the shape of the curves, forming ALS progression “subtypes.” Their method incorporated prior clinical knowledge in the way of a bias for negative trajectories — consistent with expectations for neurodegenerative disease progressions — but did not assume any linearity. “We know that linearity is not reflective of what’s actually observed,” says Ng. “The methods and models that we use here were more flexible, in the sense that, they capture what was seen in the data,” without the need for expensive labeled data and prescription of parameters.

    Primarily, they applied the model to five longitudinal datasets from ALS clinical trials and observational studies. These used the gold standard to measure symptom development: the ALS functional rating scale revised (ALSFRS-R), which captures a global picture of patient neurological impairment but can be a bit of a “messy metric.” Additionally, performance on survivability probabilities, forced vital capacity (a measurement of respiratory function), and subscores of ALSFRS-R, which looks at individual bodily functions, were incorporated.

    New regimes of progression and utility

    When their population-level model was trained and tested on these metrics, four dominant patterns of disease popped out of the many trajectories — sigmoidal fast progression, stable slow progression, unstable slow progression, and unstable moderate progression — many with strong nonlinear characteristics. Notably, it captured trajectories where patients experienced a sudden loss of ability, called a functional cliff, which would significantly impact treatments, enrollment in clinical trials, and quality of life.

    The researchers compared their method against other commonly used linear and nonlinear approaches in the field to separate the contribution of clustering and linearity to the model’s accuracy. The new work outperformed them, even patient-specific models, and found that subtype patterns were consistent across measures. Impressively, when data were withheld, the model was able to interpolate missing values, and, critically, could forecast future health measures. The model could also be trained on one ALSFRS-R dataset and predict cluster membership in others, making it robust, generalizable, and accurate with scarce data. So long as 6-12 months of data were available, health trajectories could be inferred with higher confidence than conventional methods.

    The researchers’ approach also provided insights into Alzheimer’s and Parkinson’s diseases, both of which can have a range of symptom presentations and progression. For Alzheimer’s, the new technique could identify distinct disease patterns, in particular variations in the rates of conversion of mild to severe disease. The Parkinson’s analysis demonstrated a relationship between progression trajectories for off-medication scores and disease phenotypes, such as the tremor-dominant or postural instability/gait difficulty forms of Parkinson’s disease.

    The work makes significant strides to find the signal amongst the noise in the time-series of complex neurodegenerative disease. “The patterns that we see are reproducible across studies, which I don’t believe had been shown before, and that may have implications for how we subtype the [ALS] disease,” says Fraenkel. As the FDA has been considering the impact of non-linearity in clinical trial designs, the team notes that their work is particularly pertinent.

    As new ways to understand disease mechanisms come online, this model provides another tool to pick apart illnesses like ALS, Alzheimer’s, and Parkinson’s from a systems biology perspective.

    “We have a lot of molecular data from the same patients, and so our long-term goal is to see whether there are subtypes of the disease,” says Fraenkel, whose lab looks at cellular changes to understand the etiology of diseases and possible targets for cures. “One approach is to start with the symptoms … and see if people with different patterns of disease progression are also different at the molecular level. That might lead you to a therapy. Then there’s the bottom-up approach, where you start with the molecules” and try to reconstruct biological pathways that might be affected. “We’re going [to be tackling this] from both ends … and finding if something meets in the middle.”

    This research was supported, in part, by the MIT-IBM Watson AI Lab, the Muscular Dystrophy Association, Department of Veterans Affairs of Research and Development, the Department of Defense, NSF Gradate Research Fellowship Program, Siebel Scholars Fellowship, Answer ALS, the United States Army Medical Research Acquisition Activity, National Institutes of Health, and the NIH/NINDS. More

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    In-home wireless device tracks disease progression in Parkinson’s patients

    Parkinson’s disease is the fastest-growing neurological disease, now affecting more than 10 million people worldwide, yet clinicians still face huge challenges in tracking its severity and progression.

    Clinicians typically evaluate patients by testing their motor skills and cognitive functions during clinic visits. These semisubjective measurements are often skewed by outside factors — perhaps a patient is tired after a long drive to the hospital. More than 40 percent of individuals with Parkinson’s are never treated by a neurologist or Parkinson’s specialist, often because they live too far from an urban center or have difficulty traveling.

    In an effort to address these problems, researchers from MIT and elsewhere demonstrated an in-home device that can monitor a patient’s movement and gait speed, which can be used to evaluate Parkinson’s severity, the progression of the disease, and the patient’s response to medication.

    The device, which is about the size of a Wi-Fi router, gathers data passively using radio signals that reflect off the patient’s body as they move around their home. The patient does not need to wear a gadget or change their behavior. (A recent study, for example, showed that this type of device could be used to detect Parkinson’s from a person’s breathing patterns while sleeping.)

    The researchers used these devices to conduct a one-year at-home study with 50 participants. They showed that, by using machine-learning algorithms to analyze the troves of data they passively gathered (more than 200,000 gait speed measurements), a clinician could track Parkinson’s progression and medication response more effectively than they would with periodic, in-clinic evaluations.

    “By being able to have a device in the home that can monitor a patient and tell the doctor remotely about the progression of the disease, and the patient’s medication response so they can attend to the patient even if the patient can’t come to the clinic — now they have real, reliable information — that actually goes a long way toward improving equity and access,” says senior author Dina Katabi, the Thuan and Nicole Pham Professor in the Department of Electrical Engineering and Computer Science (EECS), and a principle investigator in the Computer Science and Artificial Intelligence Laboratory (CSAIL) and the MIT Jameel Clinic.

    The co-lead authors are EECS graduate students Yingcheng Liu and Guo Zhang. The research is published today in Science Translational Medicine.

    A human radar

    This work utilizes a wireless device previously developed in the Katabi lab that analyzes radio signals that bounce off people’s bodies. It transmits signals that use a tiny fraction of the power of a Wi-Fi router — these super-low-power signals don’t interfere with other wireless devices in the home. While radio signals pass through walls and other solid objects, they are reflected off humans due to the water in our bodies.  

    This creates a “human radar” that can track the movement of a person in a room. Radio waves always travel at the same speed, so the length of time it takes the signals to reflect back to the device indicates how the person is moving.

    The device incorporates a machine-learning classifier that can pick out the precise radio signals reflected off the patient even when there are other people moving around the room. Advanced algorithms use these movement data to compute gait speed — how fast the person is walking.

    Because the device operates in the background and runs all day, every day, it can collect a massive amount of data. The researchers wanted to see if they could apply machine learning to these datasets to gain insights about the disease over time.

    They gathered 50 participants, 34 of whom had Parkinson’s, and conducted a one-year study of in-home gait measurements Through the study, the researchers collected more than 200,000 individual measurements that they averaged to smooth out variability due to the conditions irrelevant to the disease. (For example, a patient may hurry up to answer an alarm or walk slower when talking on the phone.)

    They used statistical methods to analyze the data and found that in-home gait speed can be used to effectively track Parkinson’s progression and severity. For instance, they showed that gait speed declined almost twice as fast for individuals with Parkinson’s, compared to those without. 

    “Monitoring the patient continuously as they move around the room enabled us to get really good measurements of their gait speed. And with so much data, we were able to perform aggregation that allowed us to see very small differences,” Zhang says.

    Better, faster results

    Drilling down on these variabilities offered some key insights. For instance, the researchers showed that daily fluctuations in a patient’s walking speed correspond with how they are responding to their medication — walking speed may improve after a dose and then begin to decline after a few hours, as the medication impact wears off.

    “This enables us to objectively measure how your mobility responds to your medication. Previously, this was very cumbersome to do because this medication effect could only be measured by having the patient keep a journal,” Liu says.

    A clinician could use these data to adjust medication dosage more effectively and accurately. This is especially important since drugs used to treat disease symptoms can cause serious side effects if the patient receives too much.

    The researchers were able to demonstrate statistically significant results regarding Parkinson’s progression after studying 50 people for just one year. By contrast, an often-cited study by the Michael J. Fox Foundation involved more than 500 individuals and monitored them for more than five years, Katabi says.

    “For a pharmaceutical company or a biotech company trying to develop medicines for this disease, this could greatly reduce the burden and cost and speed up the development of new therapies,” she adds.

    Katabi credits much of the study’s success to the dedicated team of scientists and clinicians who worked together to tackle the many difficulties that arose along the way. For one, they began the study before the Covid-19 pandemic, so team members initially visited people’s homes to set up the devices. When that was no longer possible, they developed a user-friendly phone app to remotely help participants as they deployed the device at home.

    Through the course of the study, they learned to automate processes and reduce effort, especially for the participants and clinical team.

    This knowledge will prove useful as they look to deploy devices in at-home studies of other neurological disorders, such as Alzheimer’s, ALS, and Huntington’s. They also want to explore how these methods could be used, in conjunction with other work from the Katabi lab showing that Parkinson’s can be diagnosed by monitoring breathing, to collect a holistic set of markers that could diagnose the disease early and then be used to track and treat it.

    “This radio-wave sensor can enable more care (and research) to migrate from hospitals to the home where it is most desired and needed,” says Ray Dorsey, a professor of neurology at the University of Rochester Medical Center, co-author of Ending Parkinson’s, and a co-author of this research paper. “Its potential is just beginning to be seen. We are moving toward a day where we can diagnose and predict disease at home. In the future, we may even be able to predict and ideally prevent events like falls and heart attacks.”

    This work is supported, in part, by the National Institutes of Health and the Michael J. Fox Foundation. More