David S. Ludwig and Mary E. Putt , 2025-04-22 09:00:00
Imagine a clinical trial with sedentary, overweight adults. One group is assigned to remain sedentary, the other to undergo intensive physical training with daily runs, calisthenics, and sports. After a week or two, the training group would probably feel sore and tired, and their endurance might be reduced. But we wouldn’t conclude that physical activity is bad for health. Clearly, we’d need a better, longer study to see the benefits.
Unfortunately, this is the exact approach taken in the clinical trials at the heart of the $170 million Nutrition for Precision Health program, as we consider in a paper published Tuesday in the BMJ, the British Medical Journal.
Nutrition for Precision Health, which is part of the NIH’s All of Us precision-medicine initiative, has an ambitious goal: to use artificial intelligence to determine what type of diet works best to prevent chronic disease for each person. To do this, research teams from across the country intend to study several thousand volunteers on three different diets. One diet is conventionally healthy, including vegetables, fruits, and whole grains. Another diet is highly processed, with lots of sugar, refined grains, and meat. The third is low-carbohydrate, based on high-fat foods and strictly limiting sugar and grains.
The investigators go to great lengths to maintain scientific rigor, providing the volunteers fully prepared meals to help them stick to the diets. Up to 1,000 will be admitted as inpatients and kept under continuous observation, to ensure they eat nothing but the prescribed diets. A huge amount of data will be collected using advanced technologies with complicated names, like “microbial metagenomics and metatranscriptomics, targeted and untargeted metabolomics,” and an “Automatic Ingestion Monitor” system.
The problem is, with all the costs and complexity, the diets can’t last long — just two weeks each. Two weeks is simply not enough time to tell us anything meaningful about how diet affects obesity and the other chronic diseases plaguing Americans today.
Consider the trial comparing “ultra-processed” and “unprocessed” diets, upon which the new research program is designed in part. During two-week inpatient stays, 20 volunteers initially ate about 600 calories more a day on the ultra-processed diet. However, this effect shrank by about 25 calories each day throughout the trial. At this rate, the diets would no longer differ after another two weeks. In a replication trial, the effect of the ultra-processed diet weakened after just one week.
Myriad factors affect how much a person eats on any particular day, among them utensil size, plate color, room temperature, and social setting. But we don’t eat with small spoons on colorless plates in a warm room with strangers in the hopes of losing much weight — these effects are transient.
Does ultra-processed food cause obesity? Maybe, but we’ll never know from short-term trials like these.
To complicate matters further, the Nutrition for Precision Health trials use a cross-over design, in which all volunteers consume all three diets in succession over several months. This design is efficient and lets investigators examine how people vary in their individual responses. But there is a big catch: The effects of one diet can bleed into the next, creating a statistical mess.
Let’s imagine what might happen with that hypothetical short-term physical activity study, if it were run as a cross-over. One group would get the vigorous activities first, becoming tired and sore. Then, during the subsequent sedentary condition, they’d rest, recover, and experience delayed benefits of exercise as the temporary side effects wore off. But the group assigned the sedentary condition first could become even less fit than they started, making the subsequent physical activities even more likely to cause side effects. This is what’s called a carry-over effect — exercise makes being sedentary appear better than it really is, whereas being sedentary makes exercise appear worse. As every statistician knows, carry-over effects can invalidate the trial.
Short-term diet trials are highly prone to these types of bias, because it takes weeks to months for the body to adapt to a major change in nutrients. For this reason, people starting a very-low-carb diet often experience fatigue and other symptoms — it’s called “keto flu.” With volunteers selected from the general population — that is, with habitually high intakes of carbohydrate — bias inevitably works against the low-carbohydrate diet.
These trials are not only inconclusive, but also potentially misleading by making a healthy diet look bad and an unhealthy diet look good. We must do better.
Can specific diets support metabolism, calm inflammation, slow aging, or protect the brain? Nutrition studies with all the bells and whistles can help answer these basic questions, but they must be long enough to allow the body to adapt, with diets and wash-out periods (the time between successive diets) of at least two months.
Ultimately, there is no substitute for long-term trials. We’d never approve a drug for obesity, diabetes, or any chronic disease based on two-week or even two-month data.
And there is no substitute for government support of nutrition science, as we’ve seen from the success of publicly funded research with tobacco-related diseases, HIV/AIDS, and birth defects, among other breakthroughs. Whereas Big Pharma can easily raise the $1 billion that may be needed to develop just one drug for just one health condition, no big company profits by preventing disease through diet. Only government can fill this gap.
With the recent budget cuts, every research dollar must count. Funding at the level of Nutrition for Precision Health could support several large-scale trials of low-carbohydrate, ultra-processed, and other diets over at least two years. These studies would lay a solid foundation for future dietary guidelines and patient care recommendations. (The government previously sponsored a slew of major low-fat diet trials, all basically failing to show any benefits, but not one low-carbohydrate diet trial of comparable magnitude.)
We’ve been debating diet for decades, even as rates of diet-related chronic diseases continue to surge. To solve this public health crisis, we need definitive research from high-quality studies. Short diet trials will never measure up to this task.
David S. Ludwig is professor of pediatrics at Harvard Medical School. Mary E. Putt is professor of biostatistics, epidemiology, and informatics at University of Pennsylvania.
