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Topics: Five Questions, Pilot Funding

Disentangling Complex Medical Outcomes

Five Questions with biostatistician Linda Valeri on the value of pilot funding eight years later.

In 2015, Linda Valeri, PhD, was a young investigator with more ideas than funding to carry them out. Armed with a doctorate in biostatistics from Harvard University, she was at that critical juncture where she needed a lab–and a research team–to put her big ideas into motion.

Enter pilot funding through our OPTICS: Open Translational Science in Schizophrenia opportunity. The $50,000 award was enough for her to hire a postdoc and kickstart an ambitious research program, Her goal: sorting out the multiple pathways that interact to bring healing–or not–to people with severe mental illness. The work led to an early-career KO1 grant and laid the foundation for her first RO1, which she was awarded in 2023.

Valeri is now an assistant professor in biostatistics at the Columbia University Mailman School of Public Health. An expert on causal inference, her focus is applying statistical methods to improve our understanding of mental health, social and environmental determinants of health, and health disparities.

Your pilot funding in 2015 came at a critical transitional stage in your career. What would you say was the value of that grant to your research?

Overall, this project was crucial for me to really delve more deeply into understanding professional care for people with severe mental illness. That has been pivotal for me to be able to continue my line of research in biostatistics and to better serve my community.

“This project was crucial for me to really delve more deeply into understanding professional care for people with severe mental illness.”

The pilot afforded a number of benefits. The first was really practical: to obtain funding to start my team before receiving a large NIH grant. It was super important for me to accelerate my productivity during a time when I was starting to generate many ideas and could not keep up with the pace of them alone. You really need a team to be able to be productive and timely in your research. Thanks to this award, I was able to hire a postdoctoral fellow and two master students. It was a very important opportunity for me to get my lab started.

The next aspect was understanding the complexity of data acquisition, privacy, and IRB agreements. It was important to understand how these mechanisms work, who are the protagonists that make these processes work, how critical it is to be in contact with them, and to never skip a step.

Third was the collaborative aspect, cross-institutional and transdisciplinary. We had a very collegial group of co-winners of the award; I was super fortunate to be able to work with these brilliant scientists. I was also able to collaborate with industry (Janssen pharmaceutical), which was my first encounter with an institution outside of academia. It was very important to learn their perspective and what they care about, in addition to the perspectives of the co-awardees.

It was also my first interface with the National Institute of Mental Health (NIMH). To understand how the NIH works in parallel with industry and clinical institutions to produce important research that informs this area of study was valuable.

So it was very much a collaborative effort, which I think was actually pretty special. I don’t think that level of collaboration across teams happens often, but it was the nature of the project in this case.

What was the essential research gap that your initial award sought to fill?

We know that severe mental illnesses such as schizophrenia and bipolar disorder are pretty complex. While antipsychotics are a key component of treatment, there’s no expectation that they are going to fix all the problems these patients have.

Many in the psychiatric community want to understand the impact of these antipsychotics not only in taming mania and depression symptoms, but also more broadly on functional outcomes and quality of life. These outcomes are becoming more and more relevant, and are increasingly regarded, together with symptoms, as primary outcomes. What could be the mechanisms which explain the potential effects or lack of effect of antipsychotics on these outcomes?

I am a biostatistician. My primary expertise is in causal inference and methods to unveil mediating mechanisms that can explain exposure or treatment effects. My specific goal was, first, to develop appropriate methodology to discover the multiple potential pathways of action related to antipsychotic medications.

How do we unravel these pathways to explain the effect of treatment on functional outcomes in a rigorous way? How do we then integrate information about these pathways across clinical trials with diverse designs, endpoints, and participant demographics?

What is the potential clinical benefit of this work?

The benefit to society is understanding whether antipsychotic medications really improve overall quality of life. If so–or not–what are the mechanisms underlying that?

We have more clearly quantified the impact of these medications on other important aspects of patients’ health, including cardiovascular and neurological health. Quantifying these potentially harmful pathways and how they interact enables clinicians to think about how they might augment these medications to minimize adverse outcomes.

This knowledge can also help inform further clinical trials. Maybe new trials would be designed with multiple arms where antipsychotics were complemented with certain diet or physical exercise interventions, or co-administered with drugs that could tame their toxicity. The next generation of clinical trials might employ new target outcomes that capture patients’ quality of life and functioning.

Your first RO1 award now applies the pathway-elucidating methodologies you developed during the pilot to an entirely different population. What is the goal?

My current R01 is serving a population of aging individuals at risk for dementia and Alzheimer’s disease. The scientific question we are addressing is whether attention to cardiovascular health for someone in their middle 20s, for example, might be more impactful than intervening later in life to prevent dementia.

“Don’t be afraid of having big ideas. Don’t be afraid of exchanging these ideas with your peers and people who are more senior than you.”

The specific goal is to develop methodologies to understand how environmental and social factors affect cognitive aging, taking into account that the disease processes mediating these effects happen over the course of a lifetime.

What is currently known comes from studies that typically examine a particular cardiovascular event at a particular time in an individual’s life and relate that to risk for a particular outcome. I would argue that this is potentially highly biased because it could mask some of the true pathways that might be operating. In practice, cardiovascular deterioration occurs along a continuum from young adulthood to middle age to late adulthood. It’s really the profile of these events–their onset and severity for example—that matters in explaining their effects.

So I bring to this question my expertise in understanding pathways and mediating mechanisms. In this case, we are really acknowledging the importance of viewing these mechanisms as multivariate disease processes occurring over time rather than discrete events.

What would you tell your younger self if you could go back and speak to her eight or 10 years ago, as a new postdoc?

You know, I just feel so lucky because I was so supported through this project. This award and all the people who were part of this award really helped me succeed.  My former mentor taught me the importance of project management. I got to work with a brilliant group of scientists. I don’t think things could have gone better.

My younger self, prior to receiving this award, could benefit from advice like “be more outspoken” and “make sure you don’t push down the ideas you have.” I would say to her: Don’t be afraid of having big ideas. Don’t be afraid of exchanging these ideas with your peers and people who are more senior than you.

And I would say: Test your gap. If someone is really keen on your ideas and your enthusiasm, just go for it. Surf the wave.

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