An Interview with Professor Nicholas Schork, Thought Leader in the Field of Single-Case Designs

Dr. Nicholas Schork is Deputy Director and Distinguished Professor of Quantitative Medicine at The Translational Genomics Research Institute (TGen), an affiliate of the City of Hope (COH) National Medical Center, and an Adjunct Professor of Medicine and Population Science at COH. He is also an Adjunct Professor of Psychiatry and Biostatistics at the University of California San Diego (UCSD) as well as Adjunct Professor of Integrative Structural and Computational Biology at Scripps Research. Prior to joining TGen, Dr. Schork held faculty positions at Scripps Research where he was co-director of the Scripps Translational Science Institute; the J. Craig Venter Institute; UCSD; and Case Western Reserve University.

Dr. Schork is a frequent participant in NIH-related steering committees and review boards. He is currently scientific director and Principal Investigator for the NIA-sponsored Longevity Consortium and Integrated Longevity OMICS initiative, two multi-million-dollar initiatives to identify and characterize genetically-mediated factors contributing to human longevity and healthspan. He is also a former member of the National Academy of Science, Engineering and Medicine (NASEM) Food and Nutrition Board and current member of the NASEM special emphasis panel on diet and disease relationships.

Dr. Schork’s interests and expertise are in quantitative human biology, genetics in particular, and integrated approaches to complex biological and medical problems. These interests include analysing large biomedical data sets, developing systems-level approaches to the analysis of biomedical data, and the design of personalized human clinical trials. Dr. Schork has published more than 550 scientific articles and book chapters on topics in biomedical and translational science, including patient-oriented clinical trials design. The ICN was delighted to interview Dr. Schork to hear his views on single-case designs.

What attracted you to the field of single-case designs in the first place? Can you tell us about your first project using these methods?

I have a background in genetics and translational genetics (i.e., trying to use genetic and genomic information to inform medical practice). 7-10% of people in the population at large possess rare or novel genetic variants that may cause them to have unique conditions of one sort or another, so exploring treatments that may benefit those people requires a more focused, patient-specific approach. I learned of N-of-1 trial methodologies in this context. Note: there are many in the biomedical science community who believe that since we are all unique at the genetic level, the N-of-1 trial mindset should be behind the care of all individuals going forward. This is the ‘precision medicine’ mindset. The first N-of-1 trial studies I was involved in were what had been referred to as the ‘1HAT’ trials of blood pressure lowering or antihypertensive medications (as opposed to the famous ‘ALLHAT’ study of antihypertensives that used population-based study methodology). What emerged in one of the 1HAT studies we pursued, which was both compelling and insightful, was that one participant showed a statistically significant drop in blood pressure while on one particular drug relative to another (we used a traditional repeated ABAB design with washout periods) but when we looked at the data more closely, that participant also lost 7-10 lbs while on the drug that lowered their blood pressure. Basically, by merely participating in the study and being asked to record information about their health and blood pressure, the participant become more health conscious and chose to lose weight at a time that happened to coincide with the last time they were on one of the medications. Basically, they ended up normalizing their blood pressure via the weight loss and were ultimately taken off their blood pressure medications!

In your opinion, what are some of the exciting developments in the field of single-case designs that you have seen during your career?

There is so much activity in the N-of-1 trials space currently. In terms of designs, I have been focusing on sequential designs among other things. Sequential designs can lead to substantial efficiency gains in the conduct of N-of-1 trials. Basically, at whatever point in an N-of-1 trial there is sufficient evidence for or against a specific hypothesis about the efficacy of an intervention, the trial is stopped, and money and time are saved. Other developments that I find exciting are techniques for aggregated N-of-1 trials, multivariate designs, and more practical designs that leverage emerging monitoring devices and minimally invasive assays.

What are some of the myths about single-case designs you have come across? Where do you think these myths come from and do you think they can be addressed?

My biggest pet peeve is that many view N-of-1 trials as novelties and not useful to address deep biomedical questions or solve clinical problems. I believe these current attitudes are rooted in legacy attitudes about how to design clinical trials and what motivated them in years past; i.e., past standard randomized clinical trials (RCTs) focused on population average effects and not necessarily individual responses. Nuanced differences between individuals that impact their response to an intervention are biological realities, however, and acceptance of this fact among many has ushered in an era of precision medicine. It is catching on, but there are many biological barriers that must be overcome to move the field forward. Ultimately, showing that something specifically tailored to an individual’s unique genetic, physiological, clinical, behavioral and exposure profile works for that individual requires study designs that assume more data is collected on them over time, as opposed to collecting less data on them and comparator individuals that could be contrasted with them.

What are some of your most recent applications of single-case designs, for example, which interventions have you been testing with single-case designs?

We are currently designing N-of-1 trials and aggregated N-of-1 trials to test the efficacy of nootropics and geroprotectors — classes of drugs/interventions focusing on cognitive enhancement and prolonging longevity, respectively.

Looking to the future, what are your predictions about future trends or breakthroughs for the field of single-case designs?

I think aggregated N-of-1 trials will be used as often as standard population-based RCTs. I also think N-of-1 trials that focus on causal relationships between interventions and outcomes to a greater degree will be a major focus in the future.

What do you think the field of single-case designs needs most?

Despite a very deep, successful, and illustrious history in education and psychology settings, N-of-1 trials need greater vetting in other clinical settings. This includes both early-stage trials in which novel interventions are tested on humans for the first time as well as very late-stage assessments of the efficacy (and correlates of efficacy) of interventions in aggregated N-of-1 trial settings. Both settings require developments in technologies for monitoring patient outcomes efficiently and reliably. I believe a few more high-profile successes of N-of-1 trials in clinical settings involving precision therapeutics will motivate more attention and, importantly, more funding of relevant studies from governmental research support institutions, foundations, and the pharmaceutical and biotechnology industries.

How could the International Collaborative Network for N-of-1 Trials and Single-Case Designs make the most impact on the field?

Expose interested parties to state-of-the-field tools for conducting studies, publications providing example applications, and a forum for discussion about the merits of various designs in different contexts, and, if possible, by sponsoring symposia and conferences about N-of-1 trials.

The ICN will be interviewing several thought leaders in the field of single-case designs over the next few months. Stay tuned!

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