Evaluating the causal impact of reproductive factors on breast cancer risk: a multivariable mendelian randomization approach
Bibliographic record
Abstract
Abstract Background Observational evidence proposes a protective effect of having children and an early age at first birth on the development of breast cancer, however the causality of this association remains uncertain. In this study we assess whether these reproductive factors impact breast cancer risk independently of age at menarche, age at menopause, adiposity measures and other reproductive factors that have been identified as being causally related to or genetically correlated with the reproductive factors of interest. Methods We used genetic data from UK Biobank (273,238 women) for reproductive factors, age at menarche and menopause, and adiposity measures, and the Breast Cancer Association Consortium for risk of overall, estrogen receptor (ER) positive and negative breast cancer as well as breast cancer subtypes. We applied univariable and multivariable Mendelian randomization (MR) to estimate direct effects of ever parous status, ages at first birth and last birth, and number of births on breast cancer risk. Results We found limited evidence of an effect of age at first birth on overall or ER positive breast cancer risk in either the univariable or multivariable analyses. While the univariable analysis revealed an effect of later age at first birth decreasing ER negative breast cancer risk (Odds ratio (OR): 0.76, 95% confidence interval:0.61-0.95 per standard deviation (SD) increase in age at first birth), this effect attenuated with separate adjustment for age at menarche and menopause (e.g., OR 0.83, 0.62-1.06 per SD increase in age at first birth, adjusted for age at menarche). In addition, we found evidence for an effect of later age at first birth on decreased human epidermal growth factor receptor 2 enriched breast cancer risk but only with adjustment for number of births (OR 0.28 (0.11-0.57) per SD increase in age at first birth). We found little evidence for direct effects of ever parous status, age at last birth or number of births on breast cancer risk, however, analyses of ever parous status and age at last birth were limited by weak instruments in the multivariable analysis. Conclusions This study found minimal evidence of a protective effect of earlier age at first birth on breast cancer risk, while identifying some evidence for an adverse effect on ER negative breast cancer risk. However, multivariable MR of ever parous status and age at last birth is limited by weak instruments which might be improved in future studies with larger sample sizes and when additional genetic variants related to reproductive factors are identified.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.051 | 0.099 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.004 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".