Supplementary Materials

Title:

Dietary characteristics associated with plasma concentrations of per- and polyfluoroalkyl

substances among adults with pre-diabetes: cross-sectional results from the Diabetes Prevention

Program Trial

Authors:

Pi-I D. Lin, ScD1,*;

Andres Cardenas, PhD, MPH2;

Russ Hauser, MD, ScD3;

Diane R. Gold, MD, MPH3,4;

Ken P. Kleinman, ScD5;

Marie-France Hivert, MD1,6;

Abby F. Fleisch, MD, MPH7,8;

Antonia M. Calafat, PhD9;

Marco Sanchez-Guerra, PhD10;

Citlalli Osorio-Yáñez, PhD11;

Thomas F. Webster, DSc12;

Edward S. Horton, MD13;

Emily Oken, MD MPH1

Affiliations:

1Division of Chronic Disease Research Across the Lifecourse, Department of Population

Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA,

USA;

2Division of Environmental Health Sciences, School of Public Health, University of California,

Berkeley, Berkeley, CA;

3Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA,

USA;

4Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA;

5Department of Biostatistics, School of Public Health and Human Sciences, University of

Massachusetts Amherst, Amherst, MA, USA;

6Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA;

7Pediatric Endocrinology and Diabetes, Maine Medical Center, Portland, ME, USA;

8Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute,

Portland, ME, USA;

9Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease

Control and Prevention, Atlanta, GA, USA;

10Department of Developmental Neurobiology, National Institute of Perinatology, Mexico City,

Mexico;

11Instituto de Investigaciones Biomédicas, Universidad Nacional Autonoma de Mexico, Ciudad

de Mexico, Mexico;

12Department of Environmental Health, Boston University School of Public Health, Boston, MA,

USA;

13Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.

*Corresponding Author:

Pi-I D. Lin, ScD

Division of Chronic Disease Research Across the Lifecourse

Department of Population Medicine

Harvard Medical School and Harvard Pilgrim Health Care Institute

401 Park Drive, Suite 401

Boston, MA 02215, USA

Phone: (617) 867-4240; Fax: (617) 867-4845

Email: debbylin@mail.harvard.edu

Contents

Table S1. Description of the food group variable available in DPP nutrient data

Table S2. Strata specific plasma PFAS concentrations among 941 prediabetic adults in US

Table S3. Adjusted percent relative difference (95% confidence interval) in the median of plasma PFAS concentrations per SD serving/day increase in intake of 27 food groups and 6 pyramid food groups among 941 prediabetic adults in US

Figure S1. Study flowchart of participants from the Diabetes Prevention Program included in this analysis

Figure S2. Spearman correlations between plasma PFAS concentrations (N=941)

Figure S3. Spearman correlations across intakes of 27 food groups (N=941)

Figure S4. Feature expression heatmap on associations of nutrient intakes with plasma PFAS concentrations (N=941)

Figure S5. Dietary patterns derived using reduced rank regression (RRR) and their associations with plasma PFAS concentration among pre-diabetic adults in the Diabetes Prevention Program (N=941). (A) Loading values for factor scores of dietary patterns; (B) Relative percent change in median plasma PFAS concentrations per standard deviation increase in factor score

Appendix 1. Diet Scores Analysis in the Diabetes Prevention Program

Table S1. Description of the food group variable available in DPP nutrient data

Variable name

Description Note (Food items included in the food groupa)

FG1 DT: Brd/Cer/Rice/Pasta(H Fib/L Fat),BL

Dark bread (including whole wheat, rye,pumpernickel, other high-fiber bread)High fiber, bran or granola cereals, shreddedwheat, Cooked cereals (including oatmeal, cream of wheat, grits, blue corn mush)

FG2 DT: Brd/Cer/Rice/Pasta(L Fib/H Fat),BL

Rice (fried).Enchiladas, tamales, tacos, tostadas, chalupas, other Mexican dishes with corn tortillas, including nachos with chile and cheese. Biscuits, scones, croissants, muffins, fry bread (pop-overs), hush puppies, fritter, puriCorn bread, corn muffins, coo-coo. Other snacks such as crackers, potato chips, corn chips, tortilla chips, pretzels, popcorn (include regular, low-fat and non-fat).

FG3 DT: Brd/Cer/Rice/Pasta(L Fib/L Fat),BL

Rice or musubi (steamed, including white, brown or wild) (including rice eaten for breakfast).Pasta, noodles (including lo mein), fideo, couscous (plain, without cheese or tomato sauce.Beef stew, pot pie, or gumbo with carrots or other vegetables.Mixed dish with beef or pork and rice (Oriental main dishes, cajun jambalaya, Spanish rice).Mixed dish with chicken or tofu and rice (Oriental main dish, cajun jambalaya, arroz con pollo). Mixed dish with seafood and rice (Oriental main dish, cajun jambalaya, paella). Spaghetti, lasagna, other pasta dishes with tomato sauce and no meat sauce. Mixed dishes with cheese but no tomato sauce (including macaroni and cheese, chilerellenos, cheese quesadillas, quiche). Burritos, including breakfast burritos, soft taco with flour tortillas.

FG4 DT: Vegetable (Tomato),BL

FG5 DT: Vegetable(Dark Green/Deep Yellow),BL

FG6 DT: Vegetable (Cruciferous),BL

FG7 DT: Vegetable (Other),BL

FG8 DT: Fruit & Fruit Juice (Citrus),BL

FG9 DT: Fruit & Fruit Juice (Other),BL

FG10 DT: Dairy (High Fat),BL

Pizza.Mixed dishes with cheese but no tomato sauce (including macaroni and cheese, chile rellenos, cheese quesadillas, quiche).

Enchiladas, tamales, tacos, tostadas, chalupas, other Mexican dishes with corn tortillas, including nachos with chile and cheese.Cream soups, such as chowders, potato, tomato, cheese.Cottage cheese, ricotta cheese, paneer (include regular, low-fat, and non-fat).Cheese (cheddar, American, cream cheese, parmesan, Velveeta, cheese spreads. including cheese on sandwiches or as snacks) (include regular, low-fat and non-fat).Whole milk and beverages with whole milk (not including milk on cereal).Non-dairy creamer in coffee or tea.

FG11 DT: Dairy (Low Fat-Inc Up to 2% Milk),BL

Plain yogurt (unflavored), raita (regular, low-fat, and non-fat).Flavored yogurt (regular, low-fat, and nonfat).2% milk and beverages with 2% milk (not including milk on cereal).Skim milk, 1% or buttermilk and beverages made with these (not including milk on cereal).Milk in coffee or tea INT: For latte & cappuccino code twice the frequency, large.

FG12 DT: Fried Fish Fried fish or fish sandwichFG13 DT: Other

Fish/ShellfishShell fish (shrimp, lobster, crab, oysters, mussels, etc., including raw). Other broiled, baked or raw fish (trout, sole, halibut, poke, grouper, etc.).Mixed dish with seafood and rice ( Oriental main dish, cajun jambalaya, paella).Fish stew or seafood gumbo.

FG14 DT: High Omega-3 Fish

Tuna fish, salmon, sardines (raw tuna or salmon, tuna salad, tuna casserole).

FG15 DT: Dried Beans,BL Refried beans (as side dish, not including those in burritos, etc).Other beans such as pintos, black beans, black-eyed peas, butter beans, red beans, garbanzos, baked beans, adzuki beans (not including soups).Lentils, dahl.Burritos, including breakfast burritos, soft taco with flour tortillas.Bean soups (including pea, lentil, black bean, potajes, miso soups).

FG16 DT: Eggs,BLFG17 DT: Meat (High

Fat),BLHamburgers, cheeseburgers, meat loaf, picadillo, carne guisada (asada).Beef (steaks, roasts, teriyaki, cube steak, beef on sandwiches, BBQ beef, etc.).Pork, including chops, roasts, ribs, barbeque, teriyaki, breaded pork chops. Mixed dish with beef or pork and rice (Oriental main dishes, cajun jambalaya, Spanish rice). Ham, ham hocks (including ham on sandwiches) INT: for ham hocks count 1/2 frequency Lamb, mutton, mutton stew, steaks or ribs.Game, including venison, rabbit, possum, squirrel. Spaghetti, lasagna, other pasta dishes with tomato and meat sauce. Burritos, including breakfast burritos, soft taco with flour tortillas. Enchiladas, tamales, tacos, tostadas, chalupas, other Mexican dishes with corn tortillas, including nachos with chile and cheese.Red chile con carne INT: When used as a condiment count 1/2 frequency.

FG18 DT: Meat (Low Game, including venison, rabbit, possum, squirrel.

Fat),BL Beef (steaks, roasts, teriyaki, cube steak, beef on sandwiches, BBQ beef, etc.).Pork, including chops, roasts, ribs, barbeque, teriyaki, breaded pork chops.Hot dogs (pork, beef, or turkey) (include regular, low fat and non-fat). Bologna, salami, spam, other lunch meats (excluding ham) (include regular, low-fat and non-fat).Hamburgers, cheeseburgers, meat loaf, picadillo, carne guisada (asada).

FG19 DT: Poultry (High Fat),BL

Fried Chicken.Chicken, turkey or wild fowl (roasted, broiled, or ground) (including teriyaki and on sandwiches).Mixed dish with chicken or tofu and rice (Oriental main dish, cajun jambalaya, arroz con pollo).

FG20 DT: Poultry (Low Fat),BL

Chicken, turkey or wild fowl (roasted, broiled, or ground) (including teriyaki and on sandwiches). Chicken or turkey stew, pot pie or gumbo with carrots or other vegetables, chicken and dumplings.Mixed dish with chicken or tofu and rice (Oriental main dish, cajun jambalaya, arroz con pollo).Freid chicken

FG21 DT: Sweets & Desserts,BL

FG22 DT: Fats & Oils,BLFG23 DT: Soy Products,BLFG24 DT: Nuts &

Seeds,BLFG25 DT: Coffee & Tea,BLFG26 DT: Meal Repl. (Inst

Bkfst/Slimfast),BLFG27 DT: Alcohol,BL

Note: aDerived using proprietary software based relevant food items at various percent depending on food and category. Information requested only for some selected food groups.

Table S2. Strata specific plasma PFAS concentrations among 941 prediabetic adults in US

Characteristics (N=941) N (%) PFOS (ng/mL) PFOA (ng/mL) PFHxS (ng/mL) EtFOSAA(ng/mL)

MeFOSAA(ng/mL)

PFNA(ng/mL)

Sex p=0.0139 p=0.0010 p<.0001 p=0.0069 p=0.4108 p<.0001 Male 329 (35.0) 28.7 (19.2, 41.2) 5.3 (3.8, 7.1) 2.9 (2.0, 4.9) 1.0 (0.6, 1.8) 1.1 (0.6, 1.7) 0.6 (0.4, 0.9) Female 612 (65.0) 26.0 (16.8, 38.9) 4.7 (3.3, 6.6) 2.0 (1.2, 3.3) 1.2 (0.7, 2.2) 1.0 (0.5, 1.7) 0.5 (0.3, 0.8)Age p=0.1498 p=0.0109 p<.0001 p<.0001 p<.0001 p=0.0054 < 40 110 (11.7) 27.6 (17.6, 40.0) 4.9 (3.4, 6.4) 1.8 (1.1, 3.1) 1.4 (0.7, 2.4) 1.4 (0.7, 2.4) 0.5 (0.4, 0.7) 40-44 107 (11.4) 24.5 (17.1, 37.8) 4.4 (2.8, 6.8) 1.9 (1.1, 3.7) 1.6 (0.7, 2.8) 1.2 (0.7, 1.9) 0.4 (0.3, 0.7) 45-49 209 (22.2) 26.1 (16.7, 41.0) 4.7 (3.3, 6.3) 2.2 (1.3, 3.8) 1.1 (0.7, 2.0) 1.1 (0.7, 1.6) 0.5 (0.3, 0.8) 50-54 164 (17.4) 27.8 (19.9, 42.7) 5.0 (3.8, 6.9) 2.2 (1.5, 3.6) 1.2 (0.8, 2.2) 1.0 (0.6, 1.7) 0.6 (0.4, 0.9) 55-59 136 (14.5) 28.2 (19.1, 41.7) 5.6 (4.0, 7.2) 2.6 (1.8, 3.7) 1.0 (0.5, 2.1) 1.0 (0.5, 1.7) 0.6 (0.4, 0.9) 60-64 104 (11.1) 27.0 (14.4, 36.1) 5.0 (3.6, 6.5) 2.6 (1.6, 4.2) 0.8 (0.5, 1.5) 0.9 (0.5, 1.6) 0.6 (0.4, 0.9) ≥ 65 111 (11.8) 25.0 (16.0, 36.0) 5.0 (3.6, 7.3) 2.9 (2.0, 4.9) 0.9 (0.5, 1.7) 0.7 (0.4, 1.3) 0.6 (0.4, 0.8)Marital status p=0.5726 p=0.0127 p=0.0463 p=0.3361 p=0.2889 p=0.1533 Married/cohabitating 638 (67.8) 26.8 (17.7, 39.1) 4.9 (3.6, 6.6) 2.4 (1.5, 4.0) 1.1 (0.6, 2.1) 1.1 (0.6, 1.7) 0.5 (0.4, 0.8) Single 110 (11.7) 28.4 (18.2, 41.0) 5.4 (3.8, 7.6) 2.0 (1.2, 3.3) 1.2 (0.7, 2.5) 1.1 (0.6, 1.7) 0.6 (0.4, 1.0) Divorced/separated 150 (15.9) 24.2 (15.0, 40.1) 4.4 (3.0, 6.4) 2.2 (1.4, 3.2) 1.0 (0.5, 1.9) 0.9 (0.5, 1.7) 0.5 (0.3, 0.8) Widowed 43 (4.6) 28.6 (14.0, 48.6) 6.4 (3.8, 8.2) 2.8 (1.6, 4.0) 1.2 (0.6, 1.8) 0.9 (0.5, 1.6) 0.5 (0.3, 0.8)Education status p=0.0002 p<.0001 p=0.0002 p=0.0072 p<.0001 p<.0001 < High school 44 (4.7) 19.4 (11.5, 32.1) 3.0 (2.2, 4.8) 1.6 (0.9, 2.0) 0.8 (0.4, 1.2) 0.4 (0.3, 1.0) 0.3 (0.2, 0.5) High school/GED 196 (20.8) 29.7 (19.8, 42.5) 5.1 (3.5, 6.8) 2.4 (1.6, 4.0) 1.2 (0.7, 2.2) 1.2 (0.6, 1.9) 0.6 (0.4, 1.0) College 462 (49.1) 26.8 (16.9, 41.3) 5.0 (3.8, 6.9) 2.4 (1.4, 3.7) 1.2 (0.6, 2.1) 1.1 (0.6, 1.7) 0.5 (0.4, 0.8) Graduate school 239 (25.4) 26.5 (17.3, 36.3) 4.7 (3.6, 6.7) 2.4 (1.6, 4.0) 1.1 (0.6, 2.1) 1.0 (0.5, 1.4) 0.6 (0.4, 0.8)Income p=0.2293 p=0.0257 p=0.0534 p=0.2035 p=0.0003 p=0.0347 <$20,000 117 (12.4) 22.6 (14.8, 37.0) 4.4 (2.9, 5.9) 2.2 (1.2, 3.4) 1.0 (0.5, 1.7) 0.8 (0.4, 1.4) 0.5 (0.3, 0.7) $20,000 - <$35,000 165 (17.5) 25.6 (16.3, 38.1) 4.6 (3.7, 6.5) 2.0 (1.3, 3.3) 1.3 (0.5, 2.4) 0.9 (0.5, 1.7) 0.5 (0.3, 0.8) $35,000 - <$50,000 191 (20.3) 27.8 (19.3, 40.0) 5.1 (3.5, 6.7) 2.3 (1.5, 3.7) 1.1 (0.7, 2.1) 1.1 (0.6, 1.8) 0.5 (0.4, 0.9) $50,000 - <$75,000 181 (19.2) 26.0 (17.6, 41.3) 5.1 (3.6, 7.2) 2.4 (1.5, 3.7) 1.1 (0.6, 2.1) 1.1 (0.6, 1.8) 0.6 (0.4, 0.9) ≥ 75,000 211 (22.4) 27.2 (18.0, 41.0) 5.2 (3.8, 6.7) 2.5 (1.6, 4.3) 1.2 (0.7, 2.2) 1.1 (0.7, 1.8) 0.6 (0.4, 0.9) Refused to answer 76 (8.1) 26.7 (16.5, 39.0) 4.8 (3.3, 6.6) 2.3 (1.6, 4.0) 1.3 (0.5, 2.2) 0.9 (0.5, 1.4) 0.5 (0.4, 0.7)Smoking Status p=0.5303 p=0.3004 p=0.9768 p=0.5554 p=0.2975 p=0.0167 Noncurrent smoker 889 (94.5) 26.7 (17.4, 40.0) 4.9 (3.5, 6.7) 2.3 (1.4, 3.8) 1.1 (0.6, 2.1) 1.0 (0.5, 1.7) 0.5 (0.4, 0.8) Current smoker 52 (5.5) 25.7 (18.8, 42.8) 5.5 (3.9, 6.9) 2.3 (1.5, 3.8) 1.5 (0.8, 2.0) 1.1 (0.7, 1.8) 0.7 (0.5, 1.3)Race/Ethnicity p=0.0007 p<.0001 p<.0001 p=0.5514 p=0.0034 p<.0001 Caucasian 545 (57.9) 26.6 (17.6, 38.1) 5.3 (3.9, 7.1) 2.5 (1.6, 4.0) 1.1 (0.6, 2.1) 1.1 (0.6, 1.7) 0.5 (0.4, 0.8) African American 177 (18.8) 31.9 (19.1, 47.7) 4.7 (3.3, 6.8) 2.5 (1.5, 4.0) 1.2 (0.7, 2.4) 1.0 (0.7, 1.8) 0.8 (0.5, 1.5) Hispanic of any race 177 (18.8) 22.7 (15.6, 35.7) 4.3 (3.0, 5.6) 1.9 (1.2, 3.2) 1.1 (0.6, 1.9) 0.8 (0.4, 1.4) 0.5 (0.3, 0.7) All other 42 (4.5) 27.2 (16.7, 42.6) 3.9 (3.0, 5.1) 1.8 (1.0, 2.5) 1.3 (0.7, 2.2) 1.1 (0.5, 1.9) 0.5 (0.4, 0.8)

*p-value comparing concentrations within strata using Kruskal-Wallis one-way analysis of variance

Table S3. Adjusteda percent relative difference (95% confidence interval) in the median of plasma PFAS concentrations per SD

serving/day increase in intake of 27 food groups and 6 pyramid food groups among 941 prediabetic adults in US

Diet variable Percent relative difference (95% CI) in median plasma concentrations of PFASFood Groups | (Mean±SD serving/day) PFOS PFOA PFHxS EtFOSAA MeFOSAA PFNABrd/Cer/Rice/Pasta(H Fib/L Fat) | (0.7±0.7) -2.3 (-6.5, 2.1) -0.3 (-4.0, 3.6) -3.8 (-8.9, 1.6) -2.3 (-8.9, 4.7) -0.6 (-6.1, 5.2) -4.7 (-9.8, 0.6)Brd/Cer/Rice/Pasta(L Fib/H Fat) | (0.6±0.6) 8.8 (3.3, 14.6)† 6.2 (1.5, 11.2)† -1.7 (-7.9, 5.0) 16.4 (7.2, 26.4)† 6.3 (-0.6, 13.8) 5.7 (-1.0, 12.9)Brd/Cer/Rice/Pasta(L Fib/L Fat) | (2.4±1.5) -1.3 (-6.7, 4.5) 0.3 (-4.6, 5.5) -3.6 (-10.2, 3.5) 2.9 (-6.0, 12.6) 3.3 (-4.1, 11.2) -1.2 (-8.0, 6.1)Vegetable (Tomato) | (0.6±0.5) -5.0 (-9.3, -0.5)* 0.1 (-3.9, 4.3) 1.3 (-4.4, 7.4) -4.0 (-10.8, 3.4) -3.2 (-8.9, 2.8) -5.8 (-11.2, -0.2)*Vegetable(Dark Green/Deep Yellow) | (0.5±0.5) 0.2 (-4.0, 4.6) -1.1 (-4.8, 2.7) -0.9 (-6.1, 4.5) -4.4 (-10.7, 2.3) -5.5 (-10.7, -0.1)* 4.3 (-1.2, 10.0)Vegetable (Cruciferous) | (0.3±0.3) -2.8 (-6.8, 1.3) -2.4 (-5.9, 1.2) -2.5 (-7.5, 2.7) -4.6 (-10.8, 1.9) -11.5 (-16.1, -6.6)† 2.1 (-3.1, 7.6)Vegetable (Other) | (1.4±0.8) -4.0 (-8.4, 0.6) 3.9 (-0.3, 8.3) 3.2 (-2.7, 9.4) 0.5 (-6.7, 8.3) -4.3 (-10.0, 1.7) -0.8 (-6.4, 5.3)Fruit & Fruit Juice (Citrus) | (0.7±0.7) -2.9 (-7.0, 1.4) -2.4 (-6.0, 1.4) 0.2 (-5.0, 5.8) -3.5 (-9.9, 3.3) -3.7 (-8.9, 1.9) 2.5 (-2.9, 8.2)Fruit & Fruit Juice (Other) | (2.2±1.9) -3.5 (-7.7, 0.8) -2.9 (-6.6, 1.0) -1.9 (-7.2, 3.7) -2.8 (-9.3, 4.3) -4.2 (-9.5, 1.5) -1.6 (-6.9, 4.0)Dairy (High Fat) | (0.6±0.8) -2.2 (-6.6, 2.5) -0.6 (-4.6, 3.5) -4.6 (-9.9, 1.0) -1.1 (-8.1, 6.4) -3.9 (-9.5, 2.0) -2.3 (-7.8, 3.6)Dairy (Low Fat-Inc Up to 2% Milk) | (1.0±1.2) -6.2 (-10.2, -2.0)† -4.1 (-7.7, -0.4)* 4.3 (-1.3, 10.1) -11.8 (-17.6, -5.5)† -7.4 (-12.4, -2.0)† -7.8 (-12.7, -2.6)†Fried Fish | (0.1±0.1) 5.5 (1.1, 10.2)* -0.7 (-4.4, 3.2) 8.1 (2.5, 14.1)† -0.7 (-7.3, 6.3) 5.6 (-0.2, 11.7) 13.6 (7.7, 19.9)†Other Fish/Shellfish | (0.1±0.2) 4.2 (-0.1, 8.7) 2.1 (-1.6, 6.0) 6.3 (0.9, 12.1)* -3.4 (-9.7, 3.3) 2.5 (-3.0, 8.2) 19.1 (13.0, 25.4)†High Omega-3 Fish | (0.1±0.2) -2.9 (-6.8, 1.2) -6.2 (-9.6, -2.8)† -4.7 (-9.5, 0.3) -2.6 (-8.8, 4.0) -3.7 (-8.7, 1.6) 0.5 (-4.6, 5.9)Dried Beans | (0.3±0.4) -2.4 (-6.9, 2.3) -2.9 (-6.9, 1.2) -3.5 (-9.0, 2.4) -1.9 (-9.0, 5.8) -5.9 (-11.5, 0.0) -5.0 (-10.5, 0.8)Eggs | (0.2±0.3) -1.1 (-5.2, 3.3) -1.0 (-4.6, 2.8) 2.1 (-3.2, 7.8) -4.7 (-10.9, 2.1) -2.0 (-7.3, 3.6) 0.0 (-5.3, 5.5)Meat (High Fat) | (0.6±0.7) 4.6 (-0.7, 10.3) 2.2 (-2.4, 7.0) 10.8 (3.8, 18.3)† 1.6 (-6.5, 10.5) 6.2 (-0.8, 13.7) 4.0 (-2.7, 11.1)Meat (Low Fat) | (0.2±0.3) 1.3 (-3.1, 5.8) 0.5 (-3.3, 4.5) 2.2 (-3.2, 7.9) 0.4 (-6.3, 7.6) 4.6 (-1.2, 10.7) 2.5 (-3.0, 8.3)Poultry (High Fat) | (0.04±0.1) 3.6 (-0.8, 8.2) -1.3 (-4.9, 2.6) 6.0 (0.5, 11.9)* -1.3 (-7.8, 5.7) -0.7 (-6.1, 5.0) 12.4 (6.5, 18.5)†Poultry (Low Fat) | (0.5±0.4) 1.6 (-2.8, 6.2) 2.2 (-1.7, 6.3) 1.6 (-3.9, 7.3) 1.3 (-5.6, 8.7) 0.8 (-4.8, 6.8) 9.6 (3.7, 15.8)†Sweets & Desserts | (1.5±1.6) 5.6 (0.4, 11.0)* 2.0 (-2.4, 6.6) -4.2 (-10.0, 1.9) 7.5 (-0.7, 16.4) 5.0 (-1.6, 12.1) 4.2 (-2.2, 10.9)Fats & Oils | (2.1±1.4) -3.1 (-7.8, 1.8) -1.0 (-5.3, 3.4) -1.4 (-7.3, 5.0) 4.0 (-3.9, 12.6) 7.1 (0.4, 14.3)* -5.5 (-11.3, 0.6)Soy Products | (0.02±0.1) -1.9 (-5.8, 2.1) -1.3 (-4.8, 2.3) -3.1 (-7.9, 1.9) -4.4 (-10.3, 2.0) -7.3 (-12.0, -2.3)† 0.3 (-4.7, 5.5)Nuts & Seeds | (0.2±0.3) -3.6 (-7.6, 0.7) -1.8 (-5.4, 2.0) -4.5 (-9.5, 0.8) -1.3 (-7.9, 5.7) -1.6 (-7.0, 4.1) -2.3 (-7.5, 3.1)Coffee & Tea | (1.8±1.8) -0.1 (-4.2, 4.2) 5.0 (1.3, 9.0)† 1.4 (-3.8, 6.8) 2.1 (-4.5, 9.1) 2.0 (-3.4, 7.7) 0.4 (-4.7, 5.9)Meal Repl. (Inst Bkfst/Slimfast) | (0.01±0.1) 0.8 (-3.2, 5.0) 0.6 (-2.9, 4.2) -1.8 (-6.6, 3.3) 0.1 (-6.2, 6.7) -2.2 (-7.2, 3.1) -1.7 (-6.5, 3.5)Alcohol | (1.2±0.5) -1.7 (-7.7, 4.7) -0.5 (-5.9, 5.2) 5.3 (-2.7, 13.9) 0.1 (-9.4, 10.6) 0.1 (-7.8, 8.7) -0.4 (-8.0, 7.8)Pyramid Food Groups | (Mean±SD serving/day)Bread, Cereal, Rice & Pasta | (3.7±2.0) 1.1 (-5.5, 8.2) 3.3 (-2.6, 9.6) -7.7 (-15.1, 0.4) 9.2 (-1.9, 21.5) 6.1 (-2.8, 15.9) -2.6 (-10.5, 6.0)Vegetable | (2.8±1.6) -4.9 (-9.4, -0.1)* 1.2 (-3.0, 5.7) 1.3 (-4.7, 7.7) -4.1 (-11.3, 3.6) -8.8 (-14.4, -2.9)† -0.6 (-6.5, 5.7)Fruit | (2.9±2.3) -4.0 (-8.2, 0.4) -3.3 (-7.0, 0.6) -1.5 (-6.9, 4.1) -3.5 (-10.2, 3.6) -4.8 (-10.2, 0.9) -0.5 (-6.0, 5.2)Milk, Yogurt & Cheese | (1.6±1.5) -7.0 (-11.3, -2.4)† -4.2 (-8.1, -0.1)* 1.1 (-4.8, 7.3) -11.8 (-18.2, -4.8)† -9.3 (-14.7, -3.5)† -8.7 (-14.0, -3.1)†Meat/Pltry/Fish/Dry Bns/Eggs/Nuts | (2.3±1.4) 3.1 (-3.4, 10.0) -1.3 (-6.8, 4.5) 8.9 (0.4, 18.1)* -4.5 (-13.9, 5.8) 0.8 (-7.4, 9.7) 17.6 (8.5, 27.6)†Fats, Oils & Sweets | (3.6±2.4) 2.5 (-3.5, 8.7) 1.0 (-4.1, 6.4) -5.1 (-11.9, 2.2) 10.7 (0.7, 21.6)* 10.9 (2.7, 19.8)† -1.0 (-8.1, 6.7)

Note: PFOS: Perfluorooctanesulfonic acid [sum of linear and branched isomers]; PFOA: perfluorooctanoic acid [sum of linear and branched isomers] expressed; PFHxS: perfluorohexane sulfonic acid expressed; EtFOSAA: N-ethyl-perfluorooctane sulfonamido

acetic acid expressed; MeFOSAA: N-methyl-perfluorooctane sulfonamido acetic acid expressed; PFNA:perfluorononanoic acid expressed. aEstimated using multivariable linear regression models with adjustment for sex, age, marital status, education, income, waist circumference, smoking status, and daily caloric intake.

*p<0.05†p<0.01

Figure S1. Study flowchart of participants from the Diabetes Prevention Program included in

this analysis

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Participants with available plasma in the biorepository for plasma PFAS concentration

measurement (N=957)

Eligible for this analysis(N=941)

Participants enrolled in the Diabetes Prevention Program

(N=3,234)

Excluded Participants with no self-reported

diet intake at baseline (N=16)

Excluded Participants in the metformin arm

(N=1073) Participants without enough

blood samples for PFAS measurements (N=1,204)

Figure S2. Spearman correlations between plasma PFAS concentrations (N=941)

Note: Median (IQR) PFAS concentrations were PFOS 32.6 (17.5, 40.3) ng/mL, PFOA 5.7 (3.5,

6.7) ng/mL, PFHxS 3.6 (1.4, 3.8) ng/mL, EtFOSAA 1.9 (0.6, 2.1) ng/mL, MeFOSAA 1.3 (0.6,

1.7) ng/mL, PFNA 0.7 (0.4, 0.8) ng/mL. The order of the correlation plot was grouped by

hierarchical clustering. Magnitudes of the spearman correlation presented by color and number.

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Figure S3. Spearman correlations across intakes of 27 food groups (N=941)

Note: Correlation coefficient (ρ) presented by color and statistically significant ρ marked by *p<0.05, **p<0.01, and ***p<0.001.

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Figure S4. Feature expression heatmap on associations of nutrient intakes with plasma PFAS

concentrations (N=941).

Note: M1 represents univariate linear regression model with nutrient intake as the independent

variable and plasma PFAS concentration as the dependent variable. M2 represents multivariate

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linear regression model adjusting for sex, age, marital status, education, income, waist

circumference, and smoking status. M3 represents M2 with additional adjustment for daily

caloric intake. Effect size represents change in plasma PFAS concentration (in standardized z-

score) per standard deviation increase in daily intake and are depicted by color intensity (blue for

negative effect and red for positive effect). Size of the circles indicates statistical significance (p-

value) and circles with a dot in the middle represent significance below the 0.2 false discovery

rate (FDR).

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Figure S5. Dietary patterns derived using reduced rank regression (RRR) and their associations

with plasma PFAS concentration among pre-diabetic adults in the Diabetes Prevention Program

(N=941). (A) Loading values for factor scores of dietary patterns; (B) Relative percent change in

median plasma PFAS concentrations per standard deviation increase in factor score.

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Note: The 6 patterns explained 27.3% of variances in baseline self-reported intakes and 8.0% of

variances in plasma concentrations of 6 PFAS chemicals. Loading value were multiplied by 100

and rounded to the nearest integer. Values greater than 20 are in blue and value greater than 40

are in dark blue. Effect estimates statically differed than 0 were marked with * (p < 0.05).

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Appendix 1. Diet Scores Analysis in the Diabetes Prevention Program

1.Description of diet scores

1a. Healthy Diet Indicator (HDI)

The Healthy Diet Indicator was originally developed in the Netherlands (Huijbregts et al. 1997;

Waijers et al. 2007) based on the WHO’s recommendation of 1990 (WHO 1991). In this study,

considering the availability of food and nutrient intake measurements in the study and the timing

of the study recruitment, we used the original HDI which used a 9-point score of four nutrients

(saturated fatty acids [SFAs], polyunsaturated fatty acids [PUFAs], mono and disaccharides, and

cholesterol) and five food groups (complex carbohydrate, dietary fiber, fruits and vegetables, and

pulses, nuts and seeds).

1b. Mediterranean Diet Score (MDS)

The original 8-point Mediterranean Diet Score (MDS) was developed by Trichopoulou et al

(Trichopoulou et al. 1995) which assessed dietary quality by intakes of seven food groups

(legumes, cereals, fruit and nuts, vegetables, meat and meat products, milk and dairy products,

alcohol) and a ratio of the mono-unsaturated fatty acids and (MUFA) and SFAs. We modified

the MDS according to method used by Sjogren 2016 to include fish intake and replace

MUFA:SFA ratio with PUFA:SFA ratio. For alcohol intake, a value of 1 was assigned to men

who consumed 10–50 g/day and to women who consumed 5-25 d/day.

1c. Low Carbohydrate High Protein Diet (LCHP)

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The Low Carbohydrate High Protein Diet (LCHP) score was calculated using method similar to

Sjogren et al. We ranked the percent of total calories from carbohydrate and percent of total

calories from protein into decile and give a score of 1 to 10 to each intake, a score of 10 was

given to the lowest decile of carbohydrate intake and the highest decile of protein intake. We

summed the score of the two intakes to create LCHP score, which ranged from 2 to 20.

1d. Dietary Approaches to Stop Hypertension (DASH)

The DASH score is calculated based on a 2100 kcal/day diet and composed of a linear index of

nine nutrient components, including sodium, cholesterol, saturated fat, total fat, protein, calcium,

magnesium, potassium, and fiber. The DASH score ranges 0 to 9. Meeting the DASH target for a

particular nutrient scores 1 point, meeting the intermediate target scores 0.5 points, and not

meeting either target scores 0 points for the nutrient. The 9-point scoring scheme was previously

developed and had been used in other studies (Gao et al. 2009; Kim and Andrade 2016; Lin et al.

1999; Mellen et al. 2008).

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Table A1. Composition of dietary scores

Cut off Scoring (points)Healthy Diet Indicator (HDI)SFA (% of energy) 0 to <10 1 (else 0)PUFA (% of energy) 3-7 1 (else 0)Protein (% of energy) 10-15 1 (else 0)Complex carbohydrate (% of energy) 50-70 1 (else 0)Mono- and disaccharides (% of energy) 0-10 1 (else 0)Dietary fibre (g/d) 27-40 1 (else 0)Fruits and vegetables (serving/d) >5 (>400 g/d) 1 (else 0)Cholesterol (mg/d) 0 to <300 1 (else 0)Pulses, nuts, and seeds (serving/d) >1 (>30g/d) 1 (else 0)Range 0 to 9

Mediterranean Diet Score (MDS)PUFA/SFA (ratio) >median 1 (else 0)Vegetable and legumes (g/d) >median 1 (else 0)Cereals (g/d) >median 1 (else 0)Fruits(g/d) >median 1 (else 0)Fish (g/d) >median 1 (else 0)Meat and meat products (g/d) <median 1 (else 0)Milk and dairy products (g/d) <median 1 (else 0)Alcohol (g/d) Women 5-25

Men 10-501 (else 0)

Range 0 to 8

Low Carbohydrate High Protein Score (LCHP)

Carbohydrate intake (g/d) Lowest to highest decile 10 to 1Protein intake (g/d) Lowest to highest decile 1 to 10Range 2 to 20

Dietary Approaches to Stop Hypertension (DASH) Target value (intermediate target)Sodium (mg/day) < 2300.0 (2300–2650) 1 (intermediate 0.5, else 0)Cholesterol (mg/day) < 149.1 (149.1–224.7) 1 (intermediate 0.5, else 0)Saturated fat (% of Kcal/day) < 6.0 (6–11) 1 (intermediate 0.5, else 0)Total fat (% of Kcal/day) < 27.0 (27–32) 1 (intermediate 0.5, else 0)Protein (% of Kcal/day) > 18.0 (16.5–18.0) 1 (intermediate 0.5, else 0)Calcium (mg/day) > 1240.0 (842.3–1240.0) 1 (intermediate 0.5, else 0)Magnesium (mg/day) > 496.7 (330.3–496.7) 1 (intermediate 0.5, else 0)Potassium (mg/day) > 4673.3 (3198.3–4673.3) 1 (intermediate 0.5, else 0)Fiber (g/day) > 30.0 (19.5–30.0) 1 (intermediate 0.5, else 0)Range 0 to 9

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