{"doi":"10.1002/ijc.33186","title":"Reply to: Comments on “<scp>One‐carbon metabolism‐related</scp> micronutrients intake and risk for hepatocellular carcinoma: A prospective cohort study”","abstract":"We thank Drs Zhang and Zhao for their interest in our study,1 and we glad that they were able to use results from our study for their sensitivity analysis. In their letter to the Editor, Zhang et al acknowledged our concern that our lack of data on hepatitis B and C virus (HBV/HCV) status could have influenced thestudy results to some extent. They also noted that most large-scale epidemiological studies do not have data on HBV/HCV status of participants. They went on to argue that studies designed to investigate associations between dietary factors and liver cancer risk are not likely to be confounded substantially by HBV/HCV status because there is no evidence supporting a strong correlation between HBV/HCV status and dietary factors. The primary objective of our study was to investigate the association between one-carbon metabolism-related micronutrients intake and risk for hepatocellular carcinoma (HCC) in a prospective cohort of 494 860 participants that included 647 HCC cases accrued over 16 years of follow-up in the NIH-AARP study.1 Specifically, we examined associations of folate, methionine and vitamins B2, B3, B6 and B12 intake and risk of HCC development in the overall sample and among a subset of participants with >3 years of follow-up to minimize confounding by subclinical HCC at baseline. All six micronutrients were analyzed simultaneously in the same model, with adjustment for multiple biological and demographic variables and known risk factors of HCC. In the overall sample, we found that higher intake of vitamin B3 (niacin) is associated with lower risk for HCC. Among participants with >3 years of follow-up, higher vitamin B3 was again associated with lower HCC risk, whereas higher vitamin B6 intake was associated with an increased risk. We stated the limitations of our study, including potential confounding by unmeasured factors, such as HBV/HCV status. It is important to note that before a factor is considered a confounder, it must satisfy three conditions: (a) it must be a risk factor for the phenotype of interest, (b) it must be associated with the exposure of interest and (c) it must be differentially distributed between cases and noncases in the study.2, 3 From the perspective of our study, HBV and HCV are well-known risk factors of HCC. However, at the time of our study, it was not entirely clear whether there is a reasonable association between HBV/HCV status and the dietary exposures of interest. We were also unable to ascertain the distribution of HBV/HCV between the cases and noncases in our study due to lack of data. Out of abundance of caution, we cited the lack of data on HBV/HCV as one of the limitations of our study, which could have confounded the results either toward or away from null. Zhang et al argue that the lack of data on HBV/HCV status should not be a major concern in our study because HBV/HCV status does not seem to correlate with dietary or lifestyle factors (eg, body mass index, smoking and alcohol use). They cited multiple studies in support of their argument and performed sensitivity analysis using results from our original study on the association between vitamin B3 intake and HCC risk to illustrate their point. They concluded that our findings are unlikely to have been influenced substantially by the lack of data on HBV/HCV status. We applaud their efforts for bringing this important observation to the forefront of the study of diet, lifestyle and liver cancer risk. S. O. A. is supported by NIH/NCI grant K01 CA237875. The authors declare no potential conflict of interest.","journal":"International Journal of Cancer","year":2020,"id":130317,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":417567,"name":"Samuel O. Antwi","orcid":"0000-0003-2372-9489","position":0,"is_corresponding":true}],"reference_count":3,"raw_metadata":null,"created_at":"2026-07-18T23:15:53.196774Z","pmid":"32621753","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}