. 2023 Aug 3;6:100117. doi: 10.1016/j.gloepi.2023.100117

Table 1.

Study Quality Assessments for Four Cohort Studies of Aspartame and Cancer. Because of study weaknesses, IARC and JECFA concluded that chance, bias, and confounding cannot be ruled out as explanations for any reported associations in these studies [[6], [7], [8]].

Citation	Cohort(s)	Exposure Assessment	Outcome Assessment	Confounding/Covariate Consideration	Study population
Stepien et al. (2016)	EPIC	Strengths • Consumption frequency ascertained Weaknesses • Self-reported • Baseline assessment only • Asked about consumption for past 12 mos • ASB not specific to aspartame • Artificially-sweetened foods (and tabletop sweeteners) not considered	Strengths • Evaluated HCC, IHBC, and GBTC separately • Up to 11.4 years of follow-up Weaknesses • No major weaknesses	Strengths • For “soft drinks (SSB + ASB)”: Adjusted for smoking, alcohol, BMI, physical activity, education, and diabetes in some analyses Weaknesses • Information on confounders were only collected at baseline • Did not adjust for hepatitis B and C infections, cirrhosis, non-alcoholic fatty liver disease, or total caloric intake • Unclear whether reported ASB-specific associations were adjusted for potential confounders, including SSB consumption or diabetes • Potential residual confounding	Strengths • Large study population (n = 477,206; 464,688 without diabetes and 12,518 with diabetes) • Cohort recruited from several EU Member States with diverse diets • Exposed and non-exposed participants drawn from the same cohort Weaknesses • >11% of the cohort was excluded from the analysis • No information on differences between included and excluded individuals
Jones et al. (2022)	NIH-AARP, PLCO	Strengths • At time of dietary data collection, aspartame was likely primary NSS in ASBs • Frequency of ASB consumption determined Weaknesses • Self-reported • Baseline assessment only • Artificially-sweetened foods (and tabletop sweeteners) not considered	Strengths • Cases confirmed through linkage to state registries (NIH-AARP and PLCO) or medical record review (PLCO) • Up to 24 years of follow-up (median 12 years) Weaknesses • PLCO cohort cases identified via self-report	Strengths • Adjusted for age at baseline, sex, race/ethnicity, BMI, smoking, alcohol use, study, total energy intake Weaknesses • Potential residual confounding • Did not adjust for SSB consumption, activity level, or family history of cancer • Information in PLCO cohort only collected at baseline, ≤5 years prior to dietary assessment • Self reported diabetes, no distinction between type 1 and 2 • Information only collected once (at baseline or at time of dietary assessment)	Strengths • Large combined cohort of 553,874 participants (506,389 without diabetes and 47,485 with diabetes) • Large number of primary liver cancer cases (839 individuals without and 221 individuals with diabetes) • Exposed and non-exposed participants drawn from the same cohort Weaknesses • Limited information on study recruitment and attrition • >30% of PLCO cohort excluded • No information on differences between included and excluded individuals
McCullough et al. (2022)	CPS-II	Strengths • Included both consumption of ASBs and tabletop NSS packet intake • Frequency of ASB consumption determined Weaknesses • Consumption data ascertained prior to regulatory approval of aspartame in carbonated beverages • Baseline assessment only	Strengths • Deaths linked to death certificates or NDI • Up to 34 years of follow-up Weaknesses • Unclear whether ascertainment of deaths was complete through 1988	Strengths • Adjusted for age, sex, race/ethnicity, smoking, marital status, education, and red and processed meat, fruit and vegetable, alcohol, and SSB consumption Weaknesses • Did not control for early adulthood BMI, total caloric intake or diabetes diagnosis after baseline • Some analyses not adjusted for BMI • Potential residual confounding	Strengths • Large study population(n = 934,777) • Exposed and non-exposed were drawn from the same cohort Weaknesses • >20% of participants excluded • No information on differences between included and excluded individuals
Debras et al. (2022)	NutriNet-Santé Study	Strengths • Included participants were surveyed every 6 mos on 3 non-consecutive 24-h days (random 2 weekdays and 1 weekend day) for 2 yrs, with at least 2 completed surveys • Food products linked to three databases to estimate NSS and aspartame exposures in food, beverages, and tabletop packets; potential reformulations considered Weaknesses • Self-reported • Appears to be baseline assessment only • A large portion of the participants only completed 2 or 3 records out of a possible 15 within the baseline period (nearly ½ of non-consumers and more than ⅓ of consumers) • Unclear how complete 24-h dietary exposure data were (mean = 5.6 measurements/person)	Strengths • Self-reported cases verified by medical records or participants' physicians. • Unreported cases identified via linkage to national health insurance system and mortality registry Weaknesses • Cancers were combined for evaluation (e.g., all cancers, obesity-related cancers, breast cancer) • Relatively short follow-up time (median = 7.8 yrs)	Strengths • Adjusted for age, sex, BMI, education, percentage of weight gain, physical activity, number of dietary records, smoking, family history of cancer, diabetes, energy intake without alcohol, daily intakes of alcohol, sodium, saturated fatty acids, fiber, sugar, fruit, vegetables, whole-grain foods, and dairy products, and acesulfame-K and sucralose intake • For breast cancer, also adjusted for age at menarche, age at first child, number of biological children, menopausal status, oral contraceptive use, and hormonal treatment for menopause Weaknesses • Potential residual confounding • Uncontrolled confounding possible in combined cancer analysis	Strengths • Exposed and non-exposed participants drawn from the same cohort • Large study population (n = 102,865), including 1,776 individuals with diabetes Weaknesses • 15.6% of the participants excluded • No information on differences between included and excluded individuals • Population recruited online and was mostly female

Citation

Cohort(s)

Exposure Assessment

Outcome Assessment

Confounding/Covariate Consideration

Study population

Stepien et al. (2016)

EPIC

Strengths

•
Consumption frequency ascertained

Weaknesses

•
Self-reported
•
Baseline assessment only
•
Asked about consumption for past 12 mos
•
ASB not specific to aspartame
•
Artificially-sweetened foods (and tabletop sweeteners) not considered

Strengths

•
Evaluated HCC, IHBC, and GBTC separately
•
Up to 11.4 years of follow-up

Weaknesses

•
No major weaknesses

Strengths

•
For “soft drinks (SSB + ASB)”: Adjusted for smoking, alcohol, BMI, physical activity, education, and diabetes in some analyses

Weaknesses

•
Information on confounders were only collected at baseline
•
Did not adjust for hepatitis B and C infections, cirrhosis, non-alcoholic fatty liver disease, or total caloric intake
•
Unclear whether reported ASB-specific associations were adjusted for potential confounders, including SSB consumption or diabetes
•
Potential residual confounding

Strengths

•
Large study population (n = 477,206; 464,688 without diabetes and 12,518 with diabetes)
•
Cohort recruited from several EU Member States with diverse diets
•
Exposed and non-exposed participants drawn from the same cohort

Weaknesses

•
>11% of the cohort was excluded from the analysis
•
No information on differences between included and excluded individuals

Jones et al. (2022)

NIH-AARP, PLCO

Strengths

•
At time of dietary data collection, aspartame was likely primary NSS in ASBs
•
Frequency of ASB consumption determined

Weaknesses

•
Self-reported
•
Baseline assessment only
•
Artificially-sweetened foods (and tabletop sweeteners) not considered

Strengths

•
Cases confirmed through linkage to state registries (NIH-AARP and PLCO) or medical record review (PLCO)
•
Up to 24 years of follow-up (median 12 years)

Weaknesses

•
PLCO cohort cases identified via self-report

Strengths

•
Adjusted for age at baseline, sex, race/ethnicity, BMI, smoking, alcohol use, study, total energy intake

Weaknesses

•
Potential residual confounding
•
Did not adjust for SSB consumption, activity level, or family history of cancer
•
Information in PLCO cohort only collected at baseline, ≤5 years prior to dietary assessment
•
Self reported diabetes, no distinction between type 1 and 2
•
Information only collected once (at baseline or at time of dietary assessment)

Strengths

•
Large combined cohort of 553,874 participants (506,389 without diabetes and 47,485 with diabetes)
•
Large number of primary liver cancer cases (839 individuals without and 221 individuals with diabetes)
•
Exposed and non-exposed participants drawn from the same cohort

Weaknesses

•
Limited information on study recruitment and attrition
•
>30% of PLCO cohort excluded
•
No information on differences between included and excluded individuals

McCullough et al. (2022)

CPS-II

Strengths

•
Included both consumption of ASBs and tabletop NSS packet intake
•
Frequency of ASB consumption determined

Weaknesses

•
Consumption data ascertained prior to regulatory approval of aspartame in carbonated beverages
•
Baseline assessment only

Strengths

•
Deaths linked to death certificates or NDI
•
Up to 34 years of follow-up

Weaknesses

•
Unclear whether ascertainment of deaths was complete through 1988

Strengths

•
Adjusted for age, sex, race/ethnicity, smoking, marital status, education, and red and processed meat, fruit and vegetable, alcohol, and SSB consumption

Weaknesses

•
Did not control for early adulthood BMI, total caloric intake or diabetes diagnosis after baseline
•
Some analyses not adjusted for BMI
•
Potential residual confounding

Strengths

•
Large study population(n = 934,777)
•
Exposed and non-exposed were drawn from the same cohort

Weaknesses

•
>20% of participants excluded
•
No information on differences between included and excluded individuals

Debras et al. (2022)

NutriNet-Santé Study

Strengths

•
Included participants were surveyed every 6 mos on 3 non-consecutive 24-h days (random 2 weekdays and 1 weekend day) for 2 yrs, with at least 2 completed surveys
•
Food products linked to three databases to estimate NSS and aspartame exposures in food, beverages, and tabletop packets; potential reformulations considered

Weaknesses

•
Self-reported
•
Appears to be baseline assessment only
•
A large portion of the participants only completed 2 or 3 records out of a possible 15 within the baseline period (nearly ½ of non-consumers and more than ⅓ of consumers)
•
Unclear how complete 24-h dietary exposure data were (mean = 5.6 measurements/person)

Strengths

•
Self-reported cases verified by medical records or participants' physicians.
•
Unreported cases identified via linkage to national health insurance system and mortality registry

Weaknesses

•
Cancers were combined for evaluation (e.g., all cancers, obesity-related cancers, breast cancer)
•
Relatively short follow-up time (median = 7.8 yrs)

Strengths

•
Adjusted for age, sex, BMI, education, percentage of weight gain, physical activity, number of dietary records, smoking, family history of cancer, diabetes, energy intake without alcohol, daily intakes of alcohol, sodium, saturated fatty acids, fiber, sugar, fruit, vegetables, whole-grain foods, and dairy products, and acesulfame-K and sucralose intake
•
For breast cancer, also adjusted for age at menarche, age at first child, number of biological children, menopausal status, oral contraceptive use, and hormonal treatment for menopause

Weaknesses

•
Potential residual confounding
•
Uncontrolled confounding possible in combined cancer analysis

Strengths

•
Exposed and non-exposed participants drawn from the same cohort
•
Large study population (n = 102,865), including 1,776 individuals with diabetes

Weaknesses

•
15.6% of the participants excluded
•
No information on differences between included and excluded individuals
•
Population recruited online and was mostly female

Notes: AARP = American Association of Retired Persons; ASB = Artificially Sweetened Beverage; BMI = Body Mass Index; CPS-II = American Cancer Society's Cancer Prevention Study II; EPIC = European Prospective Investigation into Cancer and Nutrition; GBTC = Biliary Tract Cancer; HCC = Hepatocellular Carcinoma; Hr = Hour; IHBC = Intrahepatic Bile Duct; Min = Minimum; Mos = Months; NDI = National Death Index; NIH = National Institutes of Health; NSS = Non-Sugar Sweetener; PLCO = Prostate, Lung, Colon, Ovary Screening Trial; SSB = Sugar Sweetened Beverage; Yrs = Years.