Time Restricted Eating in Survivors Trial 2.0

Calculated using the Canadian Cardiovascular Society's standardized scoring system where sex-specific points are assigned to age, systolic blood pressure (dependent on treatment status), HDL, total cholesterol, smoking and diabetes status. The range for females is 0-30% where a higher score indicates a greater risk of cardiovascular disease in the next 10 years.

Assessed by Global Deficit Score (GDS). GDS is calculated as an average score from 3 tests, as described in outcomes 3, 4 and 5 below: 1) Hopkins Verbal Learning Test, 2) Trail Making Test, and 3) Controlled Oral Word Association of the Multilingual Aphasia Exam, respecitvely. Each subtest consists of a complex scoring system, detailed below, with higher values indicating greater cognitive deficits.

Assessed by the List Sorting Working Memory Test (working memory, 0-28 score range), Picture Sequence Memory Test (episodic memory, age-adjusted scale scores) and the Hopkins Verbal Learning Test (learning, memory) which includes an immediate recall, delayed recall, and recognition accuracy from a list of 12 words. Higher scores (number of correct words out of 12) are indicative of better cognitive health.

Assessed by the Trail Making Test (attention, speed, executive function). Shorter test time on 2 forms of the test is indicative of better cognitive function.

Assessed using the Controlled Oral Word Association of the Multilingual Aphasia Exam (verbal fluency). Higher total number of correct words produced within 60 seconds for each letter is indicative of better cognitive health.

The Dimensional Change Card Sorting test will be used to assess individual ability to switch between tasks or rules.

Participants will complete: 1) balance tests (stand for 10 sec with feet a) together, b) staggered and c) one in front of the other), 2) a chair stand test (the investigators will record how long it takes for participants to complete 5 sit to stand movements), and 3) a walking speed test (the investigators will record how long it take for participants to walk 3-4 meters at their normal walking speed). 0-12 score, with higher scores indicating higher function.

Participants will be instructed to walk as far as possible for 6 minutes between two cones that will be placed 30-m apart. Walking distance in meters is the main outcome of the 6MWT.

A grip strength assessment will also be administered using a dynamometer. Grip strength is commonly used in various cancer populations, including breast cancer, as a measure of upper body strength, and an indirect estimate of whole-body strength related to physical function. Dominant and non-dominant hand grip strength will be assessed as an average of 3 measurements on each side.

Calculated using the Canadian Cardiovascular Society's standardized scoring system where sex-specific points are assigned to age, systolic blood pressure (dependent on treatment status), HDL, total cholesterol, smoking and diabetes status. The range for females is 0-30% where a higher score indicates a greater risk of cardiovascular disease in the next 10 years.

Analyzed from blood plasma using a clinical assay at a core lab

Calculated from fasting blood measures of glucose and insulin, analyzed using a clinical assay at a core lab.

Total cholesterol, low-density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides analyzed from blood serum using a clinical assay at a core lab.

Alanine transaminase (ALT), aspartate aminotransferase (AST), and albumin. Analyzed from blood serum using a clinical assay at a core lab.

BDNF will be assessed via fasted venipuncture using in-house assays

ApoE will be assessed via fasted venipuncture using in-house assays

Leptin, adiponectin, tumour necrosis factor alpha (TNF-a), Interleukin-6 (IL-6). C-reactive protein (CRP). Analyzed via fasted venipuncture using in-house assays. Markers considered together when interpreted.

VAT in the visceral region will be measured using 3T fat-water separation magnetic resonance imaging

Thigh muscle and intermuscular adipose tissue quantification. Measured using a custom 3T MRI sequence that provides fat-water separation and T1 maps for both thighs. Myosteatosis is calculated as fat fraction, the percent of inter and intramuscular fat in the total volume of the thigh muscle.

Measured using a custom 3T MRI sequence that provides fat-water separation and T1 maps for both thighs. T1 time will be corrected for fat and averaged over both thighs.

Measured using a custom 3T MRI sequence that provides fat-water separation and T1 map for the 3 widest slices through the liver. Fat fraction will be calculated as the percent fat within the volume of the liver.

Measured using a custom 3T MRI sequence that provides fat-water separation and T1 map for the 3 widest slices through the liver.

ECG-gated MOLLI sequence will be used for T1 mapping in a short-axis, mid-basal, left ventricular slice with T1 averaged across segments

3D pseudo-continuous arterial spin labelling . Will be normalized to brain volume (measured via 3D T1-weighted MPRAGE sequence).

Measured using T2 FLAIR sequence.

Measured using whole brain diffusion tensor imaging.

Measured using diffusion tensor imaging for the hippocampus.

Measured using a body composition device (BodPod) to estimate whole body fat (in kg and %) and fat free mass (in kg and %).

The Medical Body Composition Analyzer (mBCA;SECA mBCA 525) will be used to assess bioelectric impedance phase angle and skeletal muscle mass. Electrode stickers and wires will be placed on the participants hands and feet and bioimpedance measurements are carried out while the participant is laying down. A low alternating current will be provided, and impedance will be measured from electrode cables attached to 1) the participant's hands and feet, and 2) a measuring mat laying across the participant's knees.

Waist circumference at the iliac crest will be assessed using the average of two measurements using an inelastic measuring tape. Hip circumference will be measured at the widest portion of the hips, using the average of two measurements using an inelastic measuring tape.

Measurement of resting blood pressure 6 times, 60 seconds apart, in a standardized supine position, after 5 minutes of quiet rest. The investigators will average the 2nd through 6th measurements at each time point.

Aortic stiffness, measured non-invasively by pulse wave velocity, will be assessed using applanation tonometry.

Structural assessment of the carotid artery thickness will be assessed using B-mode ultrasound and artery edge-tracking software

Endothelial function will be assessed using the gold standard method of flow mediated dilation (FMD) using non-invasive duplex ultrasound (GE Vivid IQ) and edge-tracking software.

Cerebral blood flow velocity response (delta change compared to rest) of the middle cerebral artery will be assessed using transcranial Doppler ultrasound (Neurovision Transcranial Doppler System Model 500M) in accordance with recent guidelines, in response to postural changes (sit-to-stand) and exercise (squatting).

A Garmin smartwatch will be used to measure Moderate-Vigorous physical activity (total minutes at each intensity), step count, sedentary time (time spent sitting).

A Garmin smartwatch will be used to measure sleep quantity (total sleep duration)

A Garmin smartwatch will be used to measure sleep quality (total sleep efficiency).

Various components of dietary intake including macronutrients and micronutrients will be assessed through 3-day food records over 2 weekdays and 1 weekend collected using ASA-24 online system

Demographics and health history questionnaire will ask participants to report their age, ethnicity, marital status, employment status, education level, house-hold income, medical history (including pregnancy complications), personal history of common comorbid conditions, family history of cardiovascular disease, smoking status (current/former/never), current medication/supplement use, exercise and rehabilitation history. Information about prior conditions and smoking, along with the blood analysis from above will be used to calculate the 10y Framingham CVD risk score.

Health-related quality of life will be patient-reported by the Medical Outcomes Study 36-item Short Form questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. SF-36 scores are calculated into eight 0-100 scaled scores. Higher scores indicate better quality of life outcomes.

Fatigue will be assessed by the multi-dimensional fatigue inventory (MFI) validated within cancer populations. The MFI scale is a 20-item scale. Higher total scores correspond with more acute levels of fatigue.

Sleep quality will be assessed by the Pittsburgh Sleep Quality Index (19item scale), scores for each question range from 0-3, with higher scores indicating more acute sleep disturbances.

Presence and severity of anxiety and depressive symptoms will be assessed using the Hospital Anxiety and Depression Scale (HADS) and the Short Form Geriatric Depression Scale (GDS). HADS consists of two subscales (0-21 for anxiety and 0-21 for depression), 0-7 indicates a normal range, 8-10 suggests the presence of, and >11 suggests probable presence of each state. GDS consists of 15 items, 0-4 is considered normal, 5-8 indicates mild depression, 9-11 indicates moderate depression, and ≥12 indicates severe depression.

Psychosocial stress will be measured using the Perceived Stress Scale. 10-item scale, 0-4 scoring, 0-13 is considered low stress, 14-26 is considered moderate stress, and 27-40 is considered high perceived stress.

Physical activity habits will be assessed using the Recent Physical Activity Questionnaire (RPAQ) and the Duke Activity Status Index (DASI). RPAQ is a subjective measure of physical activity over the past four-weeks, and considered in three domains. DASI is 12-item scale, 0-58.2 scoreing, a higher score is considered a higher functional capacity.

Assessed by Global Deficit Score (GDS), which is calculated as an average of 3 tests: 1) Hopkins Verbal Learning Test, 2) Trail Making Test, and 3) Controlled Oral Word Association of the Multilingual Aphasia Exam. Each subtest consists of a complex scoring system, with higher values indicating greater cognitive deficits

Assessed using the Controlled Oral Word Association of the Multilingual Aphasia Exam (verbal fluency), with higher number of words produced indicative of better cognitive health.

Assessed by the List Sorting Working Memory Test (working memory, 0-28 score range), Picture Sequence Memory Test (episodic memory, age-adjusted scale scores) and the Hopkins Verbal Learning Test (learning, memory) which includes an immediate recall, delayed recall, and recognition accuracy from a list of 12 words. Higher scores (number of correct words) are indicative of better cognitive health.

Assessed by the Trail Making Test (attention, speed, executive function). Shorter test time on 2 forms of the test is indicative of better cognitive function.

The Dimensional Change Card Sorting test will be used to assess individual ability to switch between tasks or rules.

Participants will complete: 1) balance tests (stand for 10 sec with feet a) together, b) staggered and c) one in front of the other), 2) a chair stand test (the investigators will record how long it takes for participants to complete 5 sit to stand movements), and 3) a walking speed test (the investigators will record how long it take for participants to walk 3-4 meters at their normal walking speed). 0-12 score, with higher scores indicating higher function.

Participants will be instructed to walk as far as possible for 6 minutes between two cones that will be placed 30-m apart. Walking distance in meters is the main outcome of the 6MWT.

A grip strength assessment will also be administered using a dynamometer. Grip strength is commonly used in various cancer populations, including breast cancer, as a measure of upper body strength, and an indirect estimate of whole-body strength related to physical function. Dominant and non-dominant hand grip strength will be assessed as an average of 3 measurements on each side.

Measurement of height using a stadiometer, measured in metres

Assessed fasted in lab using a calibrated scale. Recorded in kilograms.

Calculated from a measurement of height and body weight to report BMI (kg/m^2)