Title: Meat consumption and mortality - results from the European Prospective Investigation into Cancer and Nutrition

Transcription

1 Author's response to reviews Title: Meat consumption and mortality - results from the European Prospective Investigation into Cancer and Nutrition Authors: Sabine Rohrmann (sabine.rohrmann@ifspm.uzh.ch) Kim Overvad (KO@SOCI.AU.DK) H Bas Bueno-de-Mesquita (bas.bueno.de.mesquita@rivm.nl) Marianne Uhre Jakobsen (MU@ipm.regionh.dk) Rikke Egeberg (egeberg@cancer.dk) Anne Tjønneland (annet@cancer.dk) Marie Christine Boutron-Ruault (boutron@igr.fr) Françoise Clavel-Chapelon (francoise.clavel@igr.fr) Laura Nailler (Laura.NAILLER@igr.fr) Vittorio Krogh (vittorio.krogh@istitutotumori.mi.it) Domenico Palli (d.palli@ispo.toscana.it) Salvatore Panico (spanico@unina.it) Fulvio Ricceri (fulvio.ricceri@hugef-torino.org) Rosario Tumino (rtumino@tin.it) Heiner Boeing (boeing@mail.dife.de) Manuela M Bergmann (bergmann@dife.de) Kuanrong Li (k.li@dkfz-heidelberg.de) Rudolf Kaaks (r.kaaks@dkfz-heidelberg.de) Kay-Tee Khaw (kk101@medschl.cam.ac.uk) Nicholas J Wareham (Nick.Wareham@mrc-epid.cam.ac.uk) Francesca L Crowe (francesca.crowe@ceu.ox.ac.uk) Timothy J Key (tim.key@ceu.ox.ac.uk) Androniki Naska (anaska@nut.uoa.gr) Antonia Trichopoulou (antonia@nut.uoa.gr) Dimitirios Trichopoulos (dtrichop@hsph.harvard.edu) Max Leenders (M.Leenders-6@umcutrecht.nl) Petra HM Peeters (P.H.M.Peeters@umcutrecht.nl) Christine Luise Parr (c.l.parr@medisin.uio.no) Dagrun Engeset (dagrun.engeset@uit.no) Guri Skeie (guri.skeie@uit.no) Paula Jakszyn (paujak@iconcologia.net) Pilar Amiano (epicss-san@ej-gv.es) Aurelio Barricarte (abarricg@cfnavarra.es) José María Huerta (jmhuerta.carm@gmail.com) M Luisa Redondo (MARIALUISA.REDONDOCORNEJO@asturias.org) María-José Sánchez (mariajose.sanchez.easp@juntadeandalucia.es) Isabel Drake (Isabel.Drake@med.lu.se) Emily Sonestedt (Emily.Sonestedt@med.lu.se) Göran Hallmans (goran.hallmans@nutrires.umu.se) Ingegerd Johansson (ingegerd.johansson@odont.umu.se)

2 Veronika Fedirko Isabelle Romieux Pietro Ferrari Teresa Norat Anne Claire Vergnau Elio Riboli Jakob Linseisen Version: 2 Date: 11 December 2012 Author's response to reviews: see over

3 Response to the reviewers comments Title: Meat consumption and mortality - results from the European Prospective Investigation into Cancer and Nutrition Reviewer: Aldo R EYNARD The relationship among high consumption of meat (mainly red varieties), increased mortality and cancer risk is still a controversial issue, since these parameters are strongly influenced by dietary habits of different regions, countries and cultures. This important multi Country research concludes with a well-written manuscript showing, with aproppiate methodologies, a bulk of well controlled results pointing out that there is a harmful association between high and long standing consumption of processed meats and increased risk of earlier mortality and also increased risk for some varieties of cancer in humans. The study was carried out with a big sample of men and women (around 450,000) belonging to the follow-up EPIC study in 10 countries of Europe. The discussion is clear, well balanced and logical with appropriate writing style in the field of Nutrition, Cancer and Epidemiology. As a Discretionary Revision, for further improvement of the manuscript. (Discussion Section, lines 20-24, from the studies into account that evaluated vegetarian and low-meat diets, it appears that a low - but not a zero - consumption of meat might be beneficial for health. This is comprehensible as meat is an important source of nutrients like protein, iron, zinc, several B-vitamins as well as vitamin A. A sub-optimal supply of some of these nutrients due to an unbalanced type of vegetarian diet seems possible and might be associated with an increased risk for morbidity and mortality. Comment: besides the macro and micro nutrients appropriated listed in this paragraph, meats are the major sources of long chained, highly unsaturated essential polyunsaturated fatty acids (LC-EFAs), which cannot be obtained in enough amounts only from vegetables sources considering the poor capability for elongation and desaturation of delta- 5 and delta- 6 enzymes in humans.it is suggested to include some comment in this regard, since the role played by lipids as macro nutrients in the context of the discussion is absent. Reply: We added on p. 17, l. 23f and essential fatty acids (linoleic acid and to minor extent also eicosapentaenoic and docosahexaenoic acid) to the above cited sentence. Please note that we excluded fish consumption from the present evaluation which is by far the most important source of EPA and DHA in the European countries included in our study. Reviewer: Jane Heyworth Reviewer's report: Thank you for the opportunity to review the article, 'Meat consumption and mortality - results from the European Prospective Investigation into Cancer and Nutrition' Sabine Rohrmann, et al. BMC Medicine Research article I believe there is still a lack of clarity about relationship between meat consumption and mortality and this large cohort provides a useful addition to evidence in this area. My comments are mainly requests for clarifications and thus fall mainly into Minor Essential Revisions category (Min ER). 1. Is the question posed by the authors new and well defined? As above the evidence relationship between meat consumption and mortality is still ambiguous and this paper provides a useful addition to this evidence.

4 Major ER 1: Given such a large study and comprehensive dietary data collection I wondered if it would have been possible to categorise processed meat into more than one type as it is collection of such diversity of products. The number of cases of case may limit the power to do. Much of the previous literature identifies processed meat as a potential risk factor it would be very useful to see some improved exposure assessment in this area. Reply: As described in the Methods section, a country-specific dietary questionnaire (or comparable instrument) has been used to assess habitual food consumption in the EPIC cohorts. Since the consumption of different types of processed meat has often been combined into a single item and the items are not always comparable between EPIC centres, we decided not deal with sub-categories of processed meat. 2. Are the methods appropriate and well described, and are sufficient details provided to replicate the work? Min ER 2: More information on the study population is required. While length of follow up is provided in the results and dates of censoring are provided in the methods, I would have found it useful to know when these cohorts commenced and what were the age ranges of the participants. Reply: We added the following information on p. 6, l. 26 ff: Participants were recruited between 1992 and 2000 depending on study center. At recruitment, men were 40-70, women years old [18]. Min ER 3: What proportion of 10,197 (p. 7, l. 5) were incomplete follow up. Reply: We deleted with incomplete follow-up information as those were already excluded from the dataset set we started with. Major ER 2: More information was needed on the time of data collection for exposures and confounders or at least clarification. Was it just data on lifestyle and food frequencies collected at baseline that was used in this analyses? Reply: All information on diet and lifestyle was collected at recruitment. We clarified this in the text (p. 7, l. 15; p. 8, l. 5). Min ER 4: What did the core set of questions ( line 10, page 7) include- were they the same or similar ( line 11)? Reply: A set of core questions was defined by the EPIC steering committee and included detailed questions on life history of tobacco smoking, alcohol drinking, current physical activity, past and current illnesses and health problems, reproductive history for both men and women, sexual maturation for women, menopause, use of contraception and of hormonal treatments (Riboli & Kaaks 1997). The questions were similar but not exactly the same in all centers. We reworded this section of the Methods section to make it clearer (p. 8. l. 5-11). Min ER 5: On page 7 it is stated that self-reported cancer, stroke or myocardial infarction were excluded. This repeated twice on page 8, paragraph 1. Reply: Thank you. We deleted the sentence on page 8. Min ER 6: Could more be included on the calculation of the PAR- did the authors need to use Poisson or pooled logistic regression models to determine the PAR? Reply: We used Cox regression to compute PAR. We changed the text starting on p. 11, l. 24, giving more details.

5 Min ER 7: Also was it possible to consider types of red meat- beef versus pork vs lamb? Reply: We do have some information on the type of red meat. As for processed meat (see answer to ER2) this information is not strictly comparable between countries, and single items could consist of different types of red meat. Thus, for the sake of precision, we did not analyze types of red meat and mortality. 3. Are the data sound and well controlled? Discretionary comment - I was pleased to see the inclusion of an analyses of meat as a continuous variable as this is better use of data. I would have preferred the authors just to present models with the continuous variables as they are not assuming a linear relationship. The presentation of both meat as a categorical and continuous variable does lead to maybe unnecessary tables and may lead to readers drawing conclusions from the categorical analyses. Reply: We prefer to present both continuous and categorical results because the results of categorical data allow for examining the shape of the association between meat consumption and mortality, i.e., non-linear effects or effects only among participants with high meat consumption. Min ER 9: Is the reference for the PAR the same as the reference for the Cox regression, that is gm or did this come from modelling meat as a continuous variable. It is stated in the abstract and discussion that 3.3% of deaths could be reduced if processed meat consumption is reduced below 20 g/day. Reply: The PAR given in our manuscript is an estimate when comparing an intake of 20+ g/day to an intake of 0-19 g/day, i.e., a categorical comparison. Min ER 10: The authors state on page 14 lines 7-10, We did not observe statistically significant effect modification by sex (Table 4). However, a high intake of processed meat was associated with significantly increased all-cause mortality among men (RR=1.35, 95% CI , 160+ vs g/day), but not among women (RR=1.38, 95% CI ; p-interaction 0.88), I think these data indicate that the risk in men and women are very similar and lack of significance for women is not that relevant. Reply: Based on the reviewer s comment we reworded this sentence now saying: We did not observe statistically significant effect modification by sex (Table 4), with similarly increased all-cause mortality in both sexes, although the association was statistically significant only among men (RR=1.35, 95% CI , 160+ vs g/day), but not among women (RR=1.38, 95% CI ; p-interaction 0.88). This may be due to the relatively small number of deaths among women in the highest processed meat consumption category (29 women; 194 men). (p. 14, l ). Major ER 3: In summarising the results of Table 4 why is BMI not discussed as this interaction was significant. Reply: In response to the Reviewer s comment, we added the following statement to the Results section (p. 14, l ): We observed a statistically significant interaction with BMI, such that the association between processed meat consumption and all-cause mortality was stronger in lean than in overweight and obese participants (p-interaction 0.04). Min ER 11: PA activity is described as having 4 categories in methods but just 2 are presented in table 1.

6 Reply: In Table 1, we combined the four categories into two (physically inactive included the categories inactive and moderately inactive, physically active included active and moderately active participants.) to make the table easier to read. We extended the footnote of Table 1. Min ER 12: Table 2 and 3 headings use RR, tables 4 and 5 use HR- be consistent I understand from the methods are all from Cox Proportional Hazards analyses. Reply: We are sorry about this inconsistency and changed all RR into HR. Min ER 13: This sentence lacked clarity as relationship between red meat and mortalisty ws not conformed: Page 13 Lin 14 These analyses partly confirmed the relationships observed in the categorical models, such that there was no statistically significant association between red meat consumption and all-cause mortality. Reply: Based on the reviewer s comment, we reworded the sentence (p. 13, l. 17ff). Min ER 14: Figure I needs a title Reply: As stated in the manuscript guidelines ( The legends should be included in the main manuscript text file at the end of the document, rather than being a part of the figure file. ), we had given that title of Figure 1 at that end of the manuscript document (p. 38). 4. Are the discussion and conclusions well balanced and adequately supported by the data? I found the lines 9-10 in the discussion lacked clarity- was the comparison in the NIH- AARP cohort of red and processed meat in one category and then processed meat alone? Reply: Red and processed meat were analyzed separately. We added the word both to the sentence to clarify this. Other Minor editorial comments Page 5 L 3 The Western world is defined as North America and Europe but Australia/NZ also falls in this category. Reply: Thank you. We added this information. Cardiovascular is sometimes spelt cardio-vascular and sometimes cardiovascular and one time is abbreviated to CVD. Reply: Thank you for pointing this out. We changed the wording to cardiovascular. Page 7 line equals not needed in line 26 as it was not used in line 23. Reply: We are sorry, but we don t understand what the reviewer refers to. Page 11, line 11 typo diseases. Reply: Changed.