Nutrition for Precision Health, Powered by the All of Us

Inclusion Criteria:

• Overall Inclusion -- Participants 18 years of age or older who have completed theprimary All of Us consent process, Electronic Health Record consent process, haveprovided at least one All of Us biospecimen suitable for DNA sequencing, and havecompleted All of Us Participant Provided Information (PPI) Modules 1-3 (Basics,Overall Health, and Lifestyle); Speak English or Spanish; Able and willing to complywith study requirements and consent to participate.

• Module 1 -- Must be willing and able to comply with Module 1 protocol; Must provideinformed 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 weeksand up to six months. This includes consuming only the foods provided during periodsof controlled feeding. Module 2 has three controlled feeding periods each lastingapproximately two weeks with at least two weeks between feeding periods, and up to 6months 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 weeksand 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 atleast two weeks between domiciled periods, and up to 6 months allowed for completionof the Module.

Exclusion Criteria:

• Module 1

1. Any change to the participant's status from the time of All of Us enrollmentthat would render them ineligible for All of Us (e.g., being incarcerated, nolonger living in the United States, or withdrawn from that study).

2. Inability to provide informed consent and engage in informed consent procedures

3. Participants who suffer from allergic reactions to, or are unwilling toconsume, any components of the liquid mixed meal (e.g., milk products, soyproducts)

4. Barriers to safe insertion of peripheral IV canula:

5. Contraindications to peripheral IV canula insertion such as local skininfection, inflammation, trauma or burns if all the upper extremities wereinvolved and there is no unaffected extremity available for IV placement;or

6. A need for long-term IV access (e.g., ESRD); or

7. Lymphedema or deep vein thrombosis (DVT) in the extremity of the IV (inthe case where another extremity is not available); or

8. Coagulopathy requiring blood thinning products; or

9. Arteriovenous (AV) graft or fistula in the extremity of the IV (in thecase where another extremity is not available)

10. Pregnancy-related conditions:

11. Gestational age precluding completion of the Module by 36 weeks. Apregnant participant should complete visit 1 by gestational age 34 weeks, 0 days and complete Module 1 by week 36.

12. Severe morning sickness limiting mixed meal tolerance test (MMTT)consumption

13. Certain types of disease states:

14. Dumping syndrome or inability to consume the volume of the MMTT liquid

15. Severe malabsorption such as history of short gut syndrome or need forparenteral or enteral nutrition

16. Less than 12-months post-metabolic or bariatric surgery

17. History of chronic pancreatitis (e.g., Cystic fibrosis) complicated byinability to tolerate the volume of the MMTT liquid

18. Health conditions requiring chronic blood transfusions or iron infusions

19. Hemoglobin <9.5 g/dL at screening

20. Serious illness and in hospice or palliative care for terminal disease

21. Swallowing issues:

22. Self-reported difficulty tolerating solids or liquids

23. Aspiration risks that require change in thickness of liquid or dietarymodifications

24. Short term antibiotic use. For example, active antibiotics use for an ongoingacute infection

25. Blood donation in the last 3 months

26. GLP-1 agonist medication (e.g. Semaglutide) instability as defined by less than 3 months of continuous use

27. Any disorder, unwillingness, or inability not covered by any other exclusioncriteria which, in the investigator's and/or team's opinion jeopardizes thesafety of the participant or others or would interfere with adherence to theprotocol.

• Module 2

1. Any change to the participant's status from the time of All of Us enrollmentthat would render them ineligible for All of Us (e.g., being incarcerated, nolonger living in the United States, or withdrawn from that study)

2. All the above mentioned exclusion criteria for Module 1 (except inability toconsume components of the liquid mixed meal)

3. Inability to provide informed consent and engage in informed consent procedures

4. Inability or failure to complete all critical elements from Module 1 (dietary,physical activity and sleep assessments, continuous glucose monitoring, MMTT)

5. Participants who are already enrolled in Module 3

6. Participants who are unlikely to be able to adhere to the protocol, based onstructured adherence assessment by a study registered dietitian or othertrained 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 metabolickitchen within allowable criteria for the test diets.

7. Participants who plan to relocate to an area not served by NPH or travel plansthat do not permit completion of the Module over a period of up to 6 months.

8. Pregnancy-related conditions:

9. Gestational age precluding completion of the Module by week 36. A pregnantparticipant must be able to begin the first dietary intervention bygestational age 26 weeks, 0 days and complete the Module by week 36.

10. High risk pregnancy defined as fetal anomaly, gestational hypertension (SBP >140 mmHg and DBP >90 mmHg), pre-eclampsia, or gestational diabetesmellitus

11. Possible ethanol (alcohol) use disorder defined by Alcohol Use DisordersIdentification Test (AUDIT) score of >15

12. History of surgery for the treatment of obesity and:

13. Self-reported dumping syndrome; or

14. Following a special diet prescribed by their practitioner

15. Uncontrolled disease states:

16. Hypertension >160/100mmHg

17. Exacerbation of underlying gastrointestinal disease, includinginflammatory bowel disease or other malabsorptive disorders

18. Decompensated cirrhosis

19. Previously diagnosed diabetes Mellitus with HbA1c >12% at screening

20. Newly diagnosed diabetes within the past three months, or HbA1c >6.5% atscreening in a person not previously diagnosed with diabetes.

21. Participants with a history of end-stage renal disease (ESRD) on hemodialysis

22. Active infectious diseases (e.g., active tuberculosis < 3 months from symptomonset or positive test, COVID < 1 month from symptom onset or positive test)

23. Malignancy (e.g., cancer) actively receiving cytotoxic chemotherapy (oral orinfusions) treatment except for nonmelanoma skin cancers during the studyperiod

24. Participants who require dietary restrictions due to a medical condition or areon a prescribed diet for underlying chronic diseases

25. Participants with type 1 or type 2 diabetes on insulin

26. Participants aged ≥ 75 years with type 2 diabetes taking prescribed medicationsthat can cause hypoglycemia (e.g. sulfonylureas, glinides), or on a prescribeddiet

27. Hospitalization for a chronic disease (e.g., congestive heart failure, stroke)within the past three months

28. Requiring transfusions/apheresis during study period

29. Participants with a current diagnosis of, or who have received treatment for,bulimia or anorexia nervosa within the past 3 years

30. 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

31. Hemoglobin <9.5 g/dL at screening

32. Myocardial infarction, invasive cardiac procedure, participation in a cardiacor acute rehabilitation programs, transient ischemic attacks, or unstablearrhythmias within the past 3 months

33. Any disorder, unwillingness, or inability not covered by any other exclusioncriteria which, in the investigator's opinion, might jeopardize the safety ofthe participant or others, or be expected to interfere with adherence to theprotocol.

• Module 3

1. All the above mentioned exclusion criteria for Modules 1 and 2

2. Participants who are already enrolled in Module 2

3. Any disorder, unwillingness, or inability not covered by any other exclusioncriteria which, in the investigator's opinion, might jeopardize the safety ofthe participant or others, or would interfere with adherence to the protocol

4. Inability to abstain from tobacco or nicotine use, vaping, alcohol, illicitdrug use, or recreational drug use for two (2) consecutive weeks whiledomiciled in the clinical unit. Nicotine gum, pouch, or patch are permitted.

5. Any condition requiring in-person treatments or visits during the study period.This will not be accommodated by the domiciling protocol; however, tele-healthvisits with the participants regular doctor are permitted.

6. Lactation or other infant care needs that cannot be accommodated whiledomiciled in the clinical unit

7. Depression as assessed by:

8. Patient Health Questionnaire (PHQ-9) score ≥ 15; or

9. Affirmative answer to PHQ-9 suicidality question: "Thoughts that you wouldbe better off dead or of hurting yourself in some way"

10. Unable to engage in daily self-care activities (e.g., bathing, transferring,toileting, feeding, dressing)

11. Uncontrolled endocrine disorders (such as Cushing's disease, pituitarydisorders, diabetes)

12. Uncontrolled pain requiring frequent or daily treatment, or adjustment ofmedication requiring weekly or bi-weekly visits. Pain medications used on anas-needed basis (PRN), such as acetaminophen or NSAIDs, are not excluded.

13. Chronic prescription medications that would pose logistical and safety issuesfor participation