Nutrition for Precision Health, Powered by the All of Us

Study Overview
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Brief Summary
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The goal of this investigational study is to develop algorithms that predict human response to foods. The main question it aims to answer are: How does varying foods and eating patterns impact one's biological and physiological responses? In what ways can novel dietary assessment measures be used to improve dietary assessments and to prescribe assessments to people in future research with increased precision? Can artificial intelligence and machine learning techniques be combined to prescribe foods and eating patterns to individuals for optimization of their health? There are 3 Modules participants may take part in: Module 1- A participant's dietary intake and accompanying nutritional status, biological and other measures will be observed over 10 days, as well as physiological responses to a liquid mixed meal tolerance test will be measured. Module 2- Participants will undergo three controlled dietary interventions provided for 14-days each and separated by washout periods of at least 14 days. Physiological responses following a diet-specific meal test will be measured. Module 3- Participants will undergo the same three dietary interventions during the same 14 day periods as Module 2 while being studied in-residence. Physiological responses following a liquid mixed meal tolerance test and a diet-specific meal test will be measured.

Detailed Description
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The NPH study design includes three modules: Module 1, a study of participants' dietary intake; Module 2, a randomized crossover trial with three dietary interventions among participants in a community-dwelling setting; and Module 3, a similar trial to Module 2 except with participants in residence, all detailed in the following text. Briefly, Module 1 will observe participants for 8-10 days while consuming their usual diet. Modules 2 and 3 will include 3 dietary interventions, each administered for 14 days, followed by a washout period between each diet. The study will be conducted at multiple sites managed by 6 clinical centers throughout the United States. An interdisciplinary team of clinical nutrition research experts will evaluate dietary assessment methods, microbial metagenomics and metatranscriptomics, targeted and untargeted metabolomics, computational and data science to advance our current understanding of nutrition which will inform personalized nutrition recommendations. The resulting artificial intelligence (AI) algorithms to predict individual responses to food will provide a foundation to create customized dietary approaches to optimize short- and long-term health.

Official Title
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Nutrition for Precision Health, Powered by the All of Us Research Program

Conditions
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Nutrition, Health, Dietary Habits

Intervention / Treatment
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* Other: Diet A
* Other: Diet B
* Other: Diet C
* Other: Liquid Mixed Meal Tolerance Test
* Other: Diet-Specific Mixed Meal Tolerance Test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overall Inclusion -- Participants 18 years of age or older who have completed the primary All of Us consent process, Electronic Health Record consent process, and genetic Return of Results consent process (any answer), have provided at least one All of Us biospecimen suitable for DNA sequencing, and have completed All of Us Participant Provided Information (PPI) Modules 1-3 (Basics, Overall Health, and Lifestyle); Speak English or Spanish; Able and willing to comply with study requirements and consent to participate. Module 1 -- Must be willing and able to comply with Module 1 protocol; Must provide informed consent for Module 1. Module 2 -- Must have completed Module 1; Must provide informed consent for Module 2; Must agree to comply with protocol over a period of approximately 10 to 12 weeks and up to six months. This includes consuming only the foods provided during periods of controlled feeding. Module 2 has three controlled feeding periods each lasting approximately two weeks with at least two weeks between feeding periods, and up to 6 months allowed for completion of the Module. Module 3 -- Must have completed Module 1; Must provide informed consent for Module 3; Must agree to comply with protocol over a period of approximately 10 to 12 weeks and up to 6 months. This includes being domiciled three times, for two weeks each, and consuming only the foods provided during the domiciled periods. There is at least two weeks between domiciled periods, and up to 6 months allowed for completion of the Module. Exclusion Criteria: Module 1 Any change to the participant's status from the time of All of Us enrollment that would render them ineligible for All of Us (e.g., being incarcerated, no longer living in the United States, or withdrawn from that study). Inability to provide informed consent and engage in informed consent procedures Participants who suffer from allergic reactions to, or are unwilling to consume, any components of the liquid mixed meal (e.g., milk products, soy products) Barriers to safe insertion of peripheral IV canula: Contraindications to peripheral IV canula insertion such as local skin infection, inflammation, trauma or burns if all the upper extremities were involved and there is no unaffected extremity available for IV placement; or A need for long-term IV access (e.g., ESRD); or Lymphedema or deep vein thrombosis (DVT) in the extremity of the IV (in the case where another extremity is not available); or Coagulopathy requiring blood thinning products; or Arteriovenous (AV) graft or fistula in the extremity of the IV (in the case where another extremity is not available) Pregnancy-related conditions: Gestational age precluding completion of the Module by 36 weeks. A pregnant participant should complete visit 1 by gestational age 34 weeks, 0 days and complete Module 1 by week 36. Severe morning sickness limiting mixed meal tolerance test (MMTT) consumption Certain types of disease states: Dumping syndrome or inability to consume the volume of the MMTT liquid Severe malabsorption such as history of short gut syndrome or need for parenteral or enteral nutrition Less than 12-months post-metabolic or bariatric surgery History of chronic pancreatitis (e.g., Cystic fibrosis) complicated by inability to tolerate the volume of the MMTT liquid Health conditions requiring chronic blood transfusions or iron infusions Hemoglobin <9.5 g/dL at screening Serious illness and in hospice or palliative care for terminal disease Swallowing issues: Self-reported difficulty tolerating solids or liquids Aspiration risks that require change in thickness of liquid or dietary modifications Short term antibiotic use. For example, active antibiotics use for an ongoing acute infection Any disorder, unwillingness, or inability not covered by any other exclusion criteria which, in the investigator's and/or team's opinion jeopardizes the safety of the participant or others or would interfere with adherence to the protocol. Module 2 Any change to the participant's status from the time of All of Us enrollment that would render them ineligible for All of Us (e.g., being incarcerated, no longer living in the United States, or withdrawn from that study) All the above mentioned exclusion criteria for Module 1 (except inability to consume components of the liquid mixed meal) Inability to provide informed consent and engage in informed consent procedures Inability or failure to complete all critical elements from Module 1 (dietary, physical activity and sleep assessments, continuous glucose monitoring, MMTT) Participants who are already enrolled in Module 3 Participants who are unlikely to be able to adhere to the protocol, based on structured adherence assessment by a study registered dietitian or other trained staff. This includes participants who have known allergic reactions to, or unwillingness to consume, study foods in Module 2 (e.g., gluten, meat, fish, nuts, dairy products) that cannot be reasonably accommodated by the metabolic kitchen within allowable criteria for the test diets. Participants who plan to relocate to an area not served by NPH or travel plans that do not permit completion of the Module over a period of up to 6 months. Pregnancy-related conditions: Gestational age precluding completion of the Module by week 36. A pregnant participant must be able to begin the first dietary intervention by gestational age 26 weeks, 0 days and complete the Module by week 36. High risk pregnancy defined as fetal anomaly, gestational hypertension (SBP >140 mmHg and DBP >90 mmHg), pre-eclampsia, or gestational diabetes mellitus Possible ethanol (alcohol) use disorder defined by Alcohol Use Disorders Identification Test (AUDIT) score of >15 History of surgery for the treatment of obesity and: Self-reported dumping syndrome; or Following a special diet prescribed by their practitioner Uncontrolled disease states: Hypertension >160/100mmHg Exacerbation of underlying gastrointestinal disease, including inflammatory bowel disease or other malabsorptive disorders Decompensated cirrhosis Previously diagnosed diabetes Mellitus with HbA1c >12% at screening Newly diagnosed diabetes within the past three months, or HbA1c >6.5% at screening in a person not previously diagnosed with diabetes. Participants with a history of end-stage renal disease (ESRD) on hemodialysis Active infectious diseases (e.g., active tuberculosis < 3 months from symptom onset or positive test, COVID < 1 month from symptom onset or positive test) Malignancy (e.g., cancer) actively receiving cytotoxic chemotherapy (oral or infusions) treatment except for nonmelanoma skin cancers during the study period Participants who require dietary restrictions due to a medical condition or are on a prescribed diet for underlying chronic diseases Participants with type 1 or type 2 diabetes on insulin Participants aged ≥ 75 years with type 2 diabetes taking prescribed medications that can cause hypoglycemia (e.g. sulfonylureas, glinides), or on a prescribed diet Hospitalization for a chronic disease (e.g., congestive heart failure, stroke) within the past three months Requiring transfusions/apheresis during study period Participants with a current diagnosis of, or who have received treatment for, bulimia or anorexia nervosa within the past 3 years Participants with major psychiatric disorders, including major depression, schizophrenia, or psychosis, who have been hospitalized in the past six (6) months or are currently enrolled in treatment programs Hemoglobin <9.5 g/dL at screening Myocardial infarction, invasive cardiac procedure, participation in a cardiac or acute rehabilitation programs, transient ischemic attacks, or unstable arrhythmias within the past 3 months Any disorder, unwillingness, or inability not covered by any other exclusion criteria which, in the investigator's opinion, might jeopardize the safety of the participant or others, or be expected to interfere with adherence to the protocol. Module 3 All the above mentioned exclusion criteria for Modules 1 and 2 Participants who are already enrolled in Module 2 Any disorder, unwillingness, or inability not covered by any other exclusion criteria which, in the investigator's opinion, might jeopardize the safety of the participant or others, or would interfere with adherence to the protocol Inability to abstain from tobacco or nicotine use, vaping, alcohol, illicit drug use, or recreational drug use for two (2) consecutive weeks while domiciled in the clinical unit. Nicotine gum, pouch, or patch are permitted. Any condition requiring in-person treatments or visits during the study period. This will not be accommodated by the domiciling protocol; however, tele-health visits with the participants regular doctor are permitted. Lactation or other infant care needs that cannot be accommodated while domiciled in the clinical unit Depression as assessed by: Patient Health Questionnaire (PHQ-9) score ≥ 15; or Affirmative answer to PHQ-9 suicidality question: Thoughts that you would be better off dead or of hurting yourself in some way Unable to engage in daily self-care activities (e.g., bathing, transferring, toileting, feeding, dressing) Uncontrolled endocrine disorders (such as Cushing's disease, pituitary disorders, diabetes) Uncontrolled pain requiring frequent or daily treatment, or adjustment of medication requiring weekly or bi-weekly visits. Pain medications used on an as-needed basis (PRN), such as acetaminophen or NSAIDs, are not excluded. Chronic prescription medications that would pose logistical and safety issues for participation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Module 1- Response to liquid mixed meal tolerance test (LMMTT) Module 2- Dietary intervention and response to diet-specific meal test Module 3- Dietary intervention and response to diet-specific meal test and LMMTT
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Module 1<br>Module 1 is approximately 10 days (minimum of 8 days) and includes two study visits and remote data collection. Visit 1 will include application of an accelerometer and continuous glucose monitoring device for remote data collection over the next 8 to 10 days. A stool sample collection kit and instructions for stool collection and completion of dietary assessments during the observation period will be provided. At Visit 2, anthropometry (height, weight and body circumferences), body composition by bioelectrical impedance (BIA), vital signs (temperature, respiratory rate and blood pressure), resting heart rate variability and grip strength will be measured. Medications will be recorded. A liquid MMTT with timed biospecimen collection (blood, urine, saliva, hair, and nails) and visual analogue assessments will be completed. Participants in Module 1 will be asked to adhere to their usual routine (e.g., diet, exercise, sleep, supplements, medication use, etc.) throughout the study. | Other: Liquid Mixed Meal Tolerance Test<br>* A liquid mixed meal tolerance test will occur in Module 1 and Module 3. For this test, participants will drink two servings of Ensure® Original, vanilla flavor. The meal will also contain acetaminophen (Tylenol) which will show how the smoothie moves through the participant's gut.<br>* Other names: LMMTT;|
| Other: Module 2<br>Module 2 is a minimum of 10 weeks long. It includes a total of six (6) study visits that occur before and after each of the three (3), 14-day dietary intervention periods (i.e., Diets A, B, and C), separated by washout periods of at least 14 days. Participants will be asked to consume only the foods provided and to adhere to their other usual routines throughout the study. At the beginning of each diet period, anthropometry (weight and circumferences), vital signs (temperature, respiratory rate and blood pressure) and body composition by BIA will be measured. Biospecimens (blood, urine and saliva) will be collected. An accelerometer and a continuous glucose monitoring device will be applied for remote data collection. A stool sample collection kit will be provided together with instructions for stool collection and dietary assessments. At the end of each diet, a diet-specific meal test with timed biospecimen blood collection and visual analogue assessments will be completed. | Other: Diet A<br>* This diet has high amounts of fruits/vegetables, whole grains, and beans, moderate amounts of dairy, meat/poultry/eggs, fish, nuts/seeds, and vegetable oils, and very low amounts of sugar sweetened drinks and desserts. Menus are developed for 1600kcal, 2100kcal, 2600kcal and 3200 kcal.<br>Other: Diet B<br>* This diet has high amounts of refined grains, meat/poultry/egg, sugar sweetened drinks, sweets, snacks, desserts, and processed foods. It has a moderate amount of dairy and low amounts of fruits/vegetables, whole grains, and fish. Menus are developed for 1600kcal, 2100kcal, 2600kcal and 3200 kcal.<br>Other: Diet C<br>* This diet has moderate-high amounts of vegetables, meat/poultry/egg, fish, nuts/seeds, and fats/oils, low amounts of fruits and dairy, and very low amounts of grains and sugars. Menus are developed for 1600kcal, 2100kcal, 2600kcal and 3200 kcal.<br>Other: Diet-Specific Mixed Meal Tolerance Test<br>* The diet-specific mixed meal tolerance test is administered at the end of each dietary intervention period in Modules 2 and 3. The meal test is a breakfast meal similar to the one eaten on the 14-day diets. Thus, three test meals will be used, one for each of the three test diets (Diet A, Diet B, Diet C). The energy (kcal) level of the breakfast meal will be based on each participant's diet prescription. The nutritional composition diet-specific MMTT will be the same test meal for all participants.<br>* Other names: Diet-Specific MMTT;|
| Other: Module 3<br>Module 3 is a minimum of 10 weeks long. It includes three (3), 14-day dietary interventions (i.e. Diets A, B, and C) completed while participants are domiciled under the supervision of study staff. At the end of each dietary intervention period, participants return to their usual residence and routine for a minimum of 2 weeks. At the beginning of each diet period, anthropometry (weight and circumferences), vital signs (temperature, respiratory rate and blood pressure) and body composition by BIA and DXA, and physical measures will be measured. Biospecimens (blood, urine and saliva) will be collected. An accelerometer and a continuous glucose monitoring device will be applied. Excluding pregnant females, participants will receive a dose of doubly labeled water. Weight and vital signs will be measured daily and questionnaires administered. A diet-specific MMTT and a separate liquid MMTT with timed blood biospecimen collection and visual analogue assessments will be completed. | Other: Diet A<br>* This diet has high amounts of fruits/vegetables, whole grains, and beans, moderate amounts of dairy, meat/poultry/eggs, fish, nuts/seeds, and vegetable oils, and very low amounts of sugar sweetened drinks and desserts. Menus are developed for 1600kcal, 2100kcal, 2600kcal and 3200 kcal.<br>Other: Diet B<br>* This diet has high amounts of refined grains, meat/poultry/egg, sugar sweetened drinks, sweets, snacks, desserts, and processed foods. It has a moderate amount of dairy and low amounts of fruits/vegetables, whole grains, and fish. Menus are developed for 1600kcal, 2100kcal, 2600kcal and 3200 kcal.<br>Other: Diet C<br>* This diet has moderate-high amounts of vegetables, meat/poultry/egg, fish, nuts/seeds, and fats/oils, low amounts of fruits and dairy, and very low amounts of grains and sugars. Menus are developed for 1600kcal, 2100kcal, 2600kcal and 3200 kcal.<br>Other: Liquid Mixed Meal Tolerance Test<br>* A liquid mixed meal tolerance test will occur in Module 1 and Module 3. For this test, participants will drink two servings of Ensure® Original, vanilla flavor. The meal will also contain acetaminophen (Tylenol) which will show how the smoothie moves through the participant's gut.<br>* Other names: LMMTT;Other: Diet-Specific Mixed Meal Tolerance Test<br>* The diet-specific mixed meal tolerance test is administered at the end of each dietary intervention period in Modules 2 and 3. The meal test is a breakfast meal similar to the one eaten on the 14-day diets. Thus, three test meals will be used, one for each of the three test diets (Diet A, Diet B, Diet C). The energy (kcal) level of the breakfast meal will be based on each participant's diet prescription. The nutritional composition diet-specific MMTT will be the same test meal for all participants.<br>* Other names: Diet-Specific MMTT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phenotypic Responses | Characterization of response phenotypes to dietary intake, meal challenges, and study diets and the factors associated with inter-individual variability in those responses. | 4 years | 
| Metabolomic and Microbiome Research | Bioinformatic identification, and characterization of diet and gut microbiome interactions for future predictive studies. | 4 years | 
| Novel Dietary Methods | Validity assessment of at least one novel dietary assessment method. There are 4 novel methods: Mobile Food Record (mFR) is an image-based method that uses before and after eating images with a credit card sized colored checkboard, referred to as a fiducial marker, to aid with food identification and portion size estimation. Automatic Ingestion Monitor v2 (AIM-2) uses a camera sensor worn on eyeglasses to automatically detect eating occurrences. Automated Self-Administered 24-Hour Dietary Assessment Tool for Food Records (ASA24 record). Participants will record foods eaten in real-time over a 24-hour period (midnight to midnight) using a secure website. Participants will be provided a weblink to access the ASA24 interface. ASA24+mFR is comprised of the ASA24 recall method assisted by images from the mFR. | 4 years |