PEER REVIEW HISTORY ...association with cor pulmonale! A study of cardiovascular mortality (both cor pulmonale and IHD) from 2015 (Kreuzer et al) has not been included in the Chinese

PEER REVIEW HISTORY

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ARTICLE DETAILS

TITLE (PROVISIONAL) Occupational exposure to silica and risk of heart disease: a

systematic review with meta-analysis.

AUTHORS Liu, Kai; Mu, Min; Fang, Kehong; Qian, Yuan; Xue, Song; Hu,

Weijiang; Ye, Meng

VERSION 1 - REVIEW

REVIEWER Theorell Töres

Stockholm University, Stress Research Institute Karolinska Institute, Dep Publ Health Sweden

REVIEW RETURNED 17-Feb-2019

GENERAL COMMENTS This Cochrane-like review of articles published since 1995 is similar to a review that we performed recently in my own country. That has not been published in English. We came to similar conclusions as this Chinese systematic review. However, we included older studies, and I notice the following deviations because of this fact: A Finnish study (Ahlman et al 1991) showed a positive association between silica exposure on one hand and both cor pulmonale and IHD on the other hand. Another study (Murray et al 1993) was significant in the predicted direction for cor pulmonale but non-significant for IHD. Cocco et al 1994 used the general population as control and found even lowered heart disease risks illustrating a point that the authors are making. An older study (Veremulen 1978) founded "exposure" in a diagnosis of silicosis with the obvious assumption that people with this diagnosis have been exposed to silica. They found no association with cor pulmonale! A study of cardiovascular mortality (both cor pulmonale and IHD) from 2015 (Kreuzer et al) has not been included in the Chinese review. It had no significant findings, and I do not know why it was not included. Maybe it was excluded for quality reasons. The authors discuss the fact that there seems to be competition between the two main outcomes, cor pulmonale and IHD. This essentially means that subjects may die because of cor pulmonale before they develop IHD and die because of that. It is therefore

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interesting that cerebrovascular disease has also been studied. One of the high quality studies (Peter et al 2013) showed a clear excess risk for cerebrovascular disease associated with silica exposure. Since there is no competition with cor puimonale for that outcome it is of considerable interest. In general the authors have done good work. The conclusions are sound. They need to discuss some of my points a little more. The language is not perfect and needs to be revised.

REVIEWER Karl-Christian Nordby

National Institute of Occupational Health

REVIEW RETURNED 12-Mar-2019

GENERAL COMMENTS The performance of a systematic review with meta-analysis in this field is needed. So the authors should be acknowledged for their effort to do this. The authors have done a well performed meta-analysis with up-to-date statistical methods. However there are several major issues with this manuscript: The choice of including studies published after 1995 may have introduced bias. Exposure in the selected studies do represent exposures all the way back to the 1940s, and it may have been a delay of publication from studies with smaller associations. At least, the authors shold report closely the results of earlier studies of interest including reviews, in order to cover also ealier publications from the same exposure period. Classifiction of heart disease are based on different entities appearing in ICD versions 6 to10 and thus in the reviewed publications, and this should have been considered in light of that the different outcome entities with similar genesis could be treated in comparable groups if warranted. For instance coronary heart disease is equivalent to ischemic heart disease, and this is not reflected in all the considerations made by the authors. A grouping of outcome that is based on perturbations of inflammation and coagulation systems; to hypertension; or related to heart conditions secondary to increased resistance in the pulmonary circulation could possibly be an option. Rheumatologic heart disease is treated separately in the manuscript, and this is probably the right way to treat this entity. The analysis of all heart disease as a common entity with a sensitivity analysis as has been done by the authors also makes the study somewhat more resilient to classification errors, and is at good choice. On the other hand, it is not very useful to conclude about «other heart diseases» if this classification stems from different primary studies with different entities being considered as «other», so if this entity should be kept as such in the meta analysis, a description in the methods section to support that different primary studies are considered to be comparable conditions related to the classification as «other heart disease» should be given. Why is the risk of pulmonary heart disease higher than inflammatory/arteriosclerotic/coronary heart disease in the analysis? – are the levels of exposure compatible with (undiagnosed) silicosis in the primary studies analysing pulmonary heart disease. Are cases of fibrotic lung disease excluded in the primary studies, or could some of the pulmonary heart disease be



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secondary to lung disease related to esposure. This should be disussed in some detail. The levels of exposure to silica in the primary studies should be discussed in light of the need to differ between indications of respirable and inhalable fractions of dust – since the systemic effects of exposure are more likely with exposure to the respirable fraction. Looking into the primary publications, it is seemingly not a linear response from exposure to RCS on the risk of heart disease in several of these. This should also be discussed thouroughly in the discussion section, since it could be due to different underlying mechanisms of low-level and high-level exposure to RCS. The influence the primary study in Chinese language (Lu Y et al., 2012) should be given some extra consideration, both regarding assosiations with outcome and classification of exposure and disease (are the levels of exposure and the classifications of disease comparable to the studies in English? – since this study shows a stronger association between exposure and outcome than the English-language publications (and the SIR according to Figure 1 is 1,76 in accordance with the English abstract of the Lu study, not 1,46 shown in Table 1). The exposure-response analysis presented by the authors did not show increased risk. Under which exposure conditions are the four studies that were subject to this analysis done, and what where the metrics of exposure (cumulative etc) used? Could differences of exposure metrics be the explanation of the failure to show exposure-response? It would be most interesting to reach a conclusion about the exposure levels the suggested observations of associations and non-associations are valid. Is the explanation of the non-association with exposure in the studies suited for exposure-response analysis that the levels of exposure in the primary studies were too low (e.g. compared to the spectre of existiing OELs for crystalline silica i different countries), or are the studies not indicating exposure to respirable crystalline silica (but also courser particles that fail to be inhaled to the deeper airways) – leading to a non-differential misclassification of exposure that would «dilute» the estimate of effect? The authors do not differ between exposure to respirable crystalline silica and other silica exposure in this manuscript, although this is clearly addressed in the primary literature. Could the authors have tried to sort out indicators of exposure to RSC from each study and present these in tables, preferably both levels in µgm-3 for 8-hours shift and a measure of cumulative exposure (Years times level)? The English language in the manuscript needs improvement with help from a native-speaking person with competence in the field – since there are many examples of unclear messages including unclear use of groupings of conditions and English terms.

VERSION 1 – AUTHOR RESPONSE

Reviewer # 1

Reviewer’s comment 1

1. This Cochrane-like review of articles published since 1995 is similar to a review that we performed

recently in my own country. That has not been published in English. We came to similar conclusions

as this Chinese systematic review. However, we included older studies, and I notice the following

deviations because of this fact: (1)A Finnish study (Ahlman et al 1991) showed a positive association



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between silica exposure on one hand and both cor pulmonale and IHD on the other hand. Another

study (Murray et al 1993) was significant in the predicted direction for cor pulmonale but non-

significant for IHD. (2)Cocco et al 1994 used the general population as control and found even

lowered heart disease risks illustrating a point that the authors are making. (3)An older study

(Veremulen 1978) founded "exposure" in a diagnosis of silicosis with the obvious assumption that

people with this diagnosis have been exposed to silica. They found no association with cor

pulmonale!

Authors’Response 1

Thank you for your comment. The objective of this this study is to provide contemporary data on the

relationship between occupational silica exposure and heart disease risk. Moreover, there was a

related review (Sjogren B 1997) published in Occup Environ Med. By setting the literature search time

to 1995, we reduced some bias or mistakes from different classifiction of heart disease based on

different entities appearing in ICD versions 6 to10.


2. A study of cardiovascular mortality (both cor pulmonale and IHD) from 2015 (Kreuzer et al) has not

been included in the Chinese review. It had no significant findings, and I do not know why it was not

included. Maybe it was excluded for quality reasons.


Thank you for your comment. This paper (Mortality from internal and external radiation exposure in a

cohort of male German uranium millers, 1946-2008.) was excluded because of low quality

assessment score, such as missing dose calculations,difficulties in disentangling effects from several

correlated radiation exposure sources; missing information on possible confounders such as smoking

and other chemicals; and lack of incidence data and low statistical power.


The language is not perfect and needs to be revised.


Thank you for your suggestion. We revised our manuscript’s English language.

Reviewer # 2


1. The choice of including studies published after 1995 may have introduced bias. Exposure in the

selected studies do represent exposures all the way back to the 1940s, and it may have been a delay

of publication from studies with smaller associations. At least, the authors shold report closely the

results of earlier studies of interest including reviews, in order to cover also ealier publications from

the same exposure period.


Thank you for your comment. The objective of this this study is to provide contemporary data on the

relationship between occupational silica exposure and heart disease risk. Moreover, we revised our

manuscript in the introduction section by reporting the earlier review published in 1997.




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2. Classifiction of heart disease are based on different entities appearing in ICD versions 6 to10 and

thus in the reviewed publications, and this should have been considered in light of that the different

outcome entities with similar genesis could be treated in comparable groups if warranted. For

instance coronary heart disease is equivalent to ischemic heart disease, and this is not reflected in all

the considerations made by the authors.


Thank you for your suggestion. We revised this point in our analyses and results sections.


3. The analysis of all heart disease as a common entity with a sensitivity analysis as has been done

by the authors also makes the study somewhat more resilient to classification errors, and is at good

choice. On the other hand, it is not very useful to conclude about «other heart diseases» if this

classification stems from different primary studies with different entities being considered as «other»,

so if this entity should be kept as such in the meta analysis, a description in the methods section to

support that different primary studies are considered to be comparable conditions related to the

classification as «other heart disease» should be given.


Thank you for your suggestion. We revised this point in the Methods-Outcome definition section.


4. Why is the risk of pulmonary heart disease higher than inflammatory/arteriosclerotic/coronary heart

disease in the analysis? – are the levels of exposure compatible with (undiagnosed) silicosis in the

primary studies analysing pulmonary heart disease. Are cases of fibrotic lung disease excluded in the

primary studies, or could some of the pulmonary heart disease be secondary to lung disease related

to esposure. This should be disussed in some detail.


Thank you for your comment. After we revised comment 3, we found the coefficient of Pulmonary

heart disease VS Ischaemic heart disease is 0.14, (95% CI = -0.06, 0.35, P = 0.160). On the other

hand, we excluded cases combing with pneumoconiosis or silicosis as possible to estimate the effect

of occupational silica exposure on heart disease risk accurately. (Methods-Outcome definition

section)


5. The levels of exposure to silica in the primary studies should be discussed in light of the need to

differ between indications of respirable and inhalable fractions of dust – since the systemic effects of

exposure are more likely with exposure to the respirable fraction. Looking into the primary

publications, it is seemingly not a linear response from exposure to RCS on the risk of heart disease

in several of these. This should also be discussed thouroughly in the discussion section, since it could

be due to different underlying mechanisms of low-level and high-level exposure to RCS.


Thank you for your comment. In our Methods-Statistical analysis section, we revised this point. using

penalized spline models, we produced exposure-response analyses for ischaemic heart disease and

pulmonary heart disease with linear association or nonlinear association analysis (determined by

testparm doses results: P for linear trend >0.05; P for nonlinear trend <0.05) with two-stage fixed-

effects (linear association) or random-effects (nonlinear association) dose-response model.



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6. The influence the primary study in Chinese language (Lu Y et al., 2012) should be given some

extra consideration, both regarding assosiations with outcome and classification of exposure and

disease (are the levels of exposure and the classifications of disease comparable to the studies in

English? – since this study shows a stronger association between exposure and outcome than the

English-language publications (and the SIR according to Figure 1 is 1,76 in accordance with the

English abstract of the Lu study, not 1,46 shown in Table 1).


Thank you for your suggestion. We searched Lu Y’s related articles again and thought this paper (Lu

Y et al., 2012) should be included. Moreover, we revise the SIR value in Table 1.


7. The exposure-response analysis presented by the authors did not show increased risk. Under

which exposure conditions are the four studies that were subject to this analysis done, and what

where the metrics of exposure (cumulative etc) used? Could differences of exposure metrics be the

explanation of the failure to show exposure-response? It would be most interesting to reach a

conclusion about the exposure levels the suggested observations of associations and non-

associations are valid. Is the explanation of the non-association with exposure in the studies suited for

exposure-response analysis that the levels of exposure in the primary studies were too low (e.g.

compared to the spectre of existiing OELs for crystalline silica i different countries), or are the studies

not indicating exposure to respirable crystalline silica (but also courser particles that fail to be inhaled

to the deeper airways) – leading to a non-differential misclassification of exposure that would «dilute»

the estimate of effect?


Thank you for your comment. The four studies were done under different exposure conditions,

including definition of low level or high level silica exposure. We added methods calculating estimate

value of exposure dose in Methods-Statistical analysis, and also added Silica types, exposure levels

in Appendix Table B, Table 2 (including subgroup analyses and meta-regression analyses) and

discussion sections. While the metrics of exposure extracted from included papers were similar in our

exposure-response analysis:Cumulative silica exposure. Our results of exposure-response analyses

confirmed the excess risk of pulmonary heart disease in workers exposed to silica, but no excess risk

evidence was found for ischaemic heart disease at the same exposure levels. What’s more, additional

sentences and one related latest paper have been included at the end of discussion section to deeply

explain the outcome.


8. The English language in the manuscript needs improvement with help from a native-speaking

person with competence in the field – since there are many examples of unclear messages including

unclear use of groupings of conditions and English terms.


Thank you for your comment. We revised our manuscript’s English language.



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VERSION 2 – REVIEW


National Institute of Occupational Health, Oslo, Norway

REVIEW RETURNED 19-Jul-2019

GENERAL COMMENTS Review of Revision 1. Thank you for revising your manuscript. The English language of the manuscript has been improved in the revision, but there are still a lot of unclear sentences, grammatical errors, and wrong use of prepositions. I suggest again that the manuscript should be carefully revised by a native English-speaking person in order to make the proper corrections. Although I am not a native English-speaking person, I have suggested a number of minor corrections related to the language that still need to be considered. Major issues with the revised manuscript. Page 4/line 15-23. As this reads now, 4 authors independently read and scored articles, and disagreements were solved by involving a third person. This does not make sense. Also the sentence “…From studying to using a piloted data collection form,…” does not make sense. Do you mean “Four authors participated in the scoring of articles. Two authors independently read and scored each article, filling in information in a piloted data collection form. Disagreements were solved by discussions with a third author”? Or was the scoring performed by 4 authors, with a 5th person as an adjudicator (was this 5th person also one of the authors?). P 5/l 18-25. The sentence reading “101 studies’ population weren’t occupational exposure to silica, 50 were repetitive research results, 25 Occupational exposure not specified in protocol (ie: Koskela. Etc,34 the level of low (< 20 mg/m3) means for non-exposed population?) and 27 other studies were excluded because the risk of exposed group was calculated by the populations of the silicosis instead of occupational silica-exposed populations.” Is hard to read, and probably include several imprecise items. I have several objections to this section: Firstly, did you mean: “We excluded 101 studies that did not include occupational exposure to silica..” ? “50 studies were repetitive research results” needs further explanation – do you mean results were published in several articles, and only the original publication was included? “25 Occupational exposure not specified in protocol (ie: Koskela. Etc,”. Here it is not possible to sort out what you really mean. The abbreviation i.e. (that is) seems misplaced – did you mean e.g. (for example)?, and the “etc” must be removed here. What is the difference between the 101 studies not including occupational exposure to silica and the mentioned 25 studies here? “34 the level of low (< 20 mg/m3) means for non-exposed population?) and 27 other studies were excluded because the risk of exposed group was calculated by the populations of the silicosis instead of occupational silica-exposed populations.” The first part of this needs explanation. 20 mg/m3 must be considered an overwhelmingly high exposure If it refers to respirable crystalline silica, and do not indicate a non-exposed population – or did you



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mean non-occupationally exposed population (and thus probably 20 micrograms per cube?)? 6/5-8. Now reads: “Sensitivity analysis indicated that eleven studies were the main origin of heterogeneity.10-13, 16, 20, 21, 23-27 The heterogeneity decreased after the exclusion of these five data (I2 = 41.9%). However, the corresponding pooled relative risk estimate still kept significant (RR = 1.14, 95% CI = 1.10, 1.18).” Please clarify what you mean here ; if eleven studies were the main origin of heterogeneity, what is the intellectual link to the next sentence describing that excluding five data (do you mean studies?), and not after excluding all eleven studies from the meta analysis of sensitivity. Please, also give the estimate of heterogeneity both before and after exclusion of the relevant studies of main origin to heterogeneity, and not only I squared after exclusion. In the last sentence (6/8), to me it would be better to say that the meta risk estimate (not pooled estimate) remained significant after exclusion of the studies that were the main origin of heterogeneity between studies. If it is the meta regression that is presented in the full data set, it seems misplaced (why put this under a heading of Subgroup analysis?). If it is the comparison between estimated coefficients of regression between silica exposure and different types of outcome, to me this seems to add little to the presentation (“how much more significant is one outcome compared to another outcome hardly adds substantially to the information obtained by the study). Also, describing this as two situations adds to the confusion that I feel about this. Seemingly, like in table 2 you are dealing with additive relative risk values here, and this should be explained for clarity. The point described under “situation (2)” could be of interest, but needs a clearer presentation to be intelligible. The last part of the section stating: “(2) Coefficient of study quality assessment score 7 VS 6 was -0.28 (95% CI = -0.54, -0.03, P = 0.033), which indicated that the greater the proportion of heart disease in cohort studies of low quality score, the higher pooled RR for low quality score cohort studies compared with heart disease (Table 2).” also needs improvement – it is not possible to follow the intellectual content here. The indicator of study quality is suggestedly not a coefficient, but the difference between studies scored with quality =7 vs quality=6 is interesting to know. Also; the statement that the greater the proportion of heart disease …. The higher pooled RR (meta RR).. is not very surprising. If you want to say something about differences according to study quality, perhaps you can say” Comparing studies with quality score=7 to quality score=6, we found that the studies of higher quality had a lower estimate of effect from silica exposure, and give the estimates of the effects. But, would it not be more easy to read if you kept the estimates here on a ratio level, and gave the RRmeta of studies obtaining a quality score of 7 compared to the RRmeta of studies obtaining 6? 6/16-28. In the description of the results from meta-regression analysis, it is hard to follow the meaning of this last section. Therefore, this reviewer is not able to suggest a sound presentation of what the authors have done and observed. Table 2. 15/4. Heading “I2 Value (%)” should read “I2 value (%)”, “P Value for Heterogeneity” should read “p value for heterogeneity”, “Pooled



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RR” should better read “Meta RR”, “P-Value for Pooled RR” should read “p value for meta RR”. The rationale for the column to the right, named beta of regression metat-regression analysis seems unclear to this reviewer. Is the idea that “other heart disease with beta =1.00 is not affected by silica exposure and the other outcomes are related to that “reference”. If you wish to keep this column in the table, it need a good description with rationale in the methods chapter as well as an interpretation in the discussion. Seemingly, the chosen strategy for analysis here only identified differences between ischaemic heart disease and other heart disease (if I understand the table right). To me, it seems a better strategy to delete this column. Minor issues. Abstract. Some sentences can be simplified. E.g. p 1/l 47 “In this meta-analysis, the overall risk of heart disease was found increased (10%) significantly among silica-exposed workers (pooled RR = 1.10, 95% CI = 1.05, 1.15)” should read “ In this meta analysis, we identified an overall risk of heart disease (pooled RR=1.10, 95 % CI 1.05, 1.15)”. Also, there is no need to repeat that the study is a systematic review with meta analysis several times during the abstract. 2/27 Heading Intrduction should read Introduction. 2/32 reclassified should read classified. 2/35 the use of the expression “workers’ negligence of self protection” to my opinion places too much responsibility on the worker – for instance: are the authors sure that the need to use protective means are understood, are the equipment compatible with the workplace and the need to consume the needed extra time that will unevitably be connected with the use of personal protection; included the slowing of work implying physical exertion? If not so, I suggest a more balanced view of why workers do not use relevant personal protection equipment when working in dusty environments, eventually if you withheld the contention about worker’ negligence, it shoud be supported by relevant references about whether suboptimal use of PPE should be ascribed to workers “negligence”. 2/44 “silica-exposed diseases” should read “ diseases at increased risk due to silica exposure”. 2/48 “Nevertheless, the link between silica exposure and the relative risk of heart disease mortality ...” Should read …”Nevertheless, the link between silica exposure and heart disease mortality….” 2/ 53&59. I prefer that “researches” reads “research”. Methods. 3/34 “The exposure of interest was silica-exposed populations..” should read “The exposure of interest was silica dust. We included studies of silica-related occupation….” 3/38 - 44 Please do not use capital letters unless after full stop, except TCE, JEM, and SD). 3/54 “Furthermore, we excluded cases combing with pneumoconiosis or silicosis as much as possible” should probably read “Furthermore, we excluded cases of heart disease combining with pneumoconiosis or silicosis when this was possible to infer from information in the primary study”. This para also leaves a question about how cases could be excluded (did you exclude studies where a diagnostic group combining pneumoconiosis or silicosis with heart disease was used? Cases could not be excluded on a case-to-case basis since this was a meta-analysis?



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3/58 in line with the latter comment: “That’s to say, we only included the cases of nonsilicotics and underlying death cause in two of these included literatures respectively”. Is this a specification of the former paragraph? You cannot include the “cases of nonsilicotics and underlying death cause..” – this has no intelligible interpretation. Please look closely into the meaning of the paragraphs from 3/54 on. 4/2 ..”about” should probably read “for”. 4/10 “Giving each satisfactory answer could receive one or two point, only high methodological quality articles were considered if the article was with a score of six or more.” Should probably read “We scored each study with zero, one, or two point for each item, the sum of scores for each study was used to classify the quality of the study, and a score of six or greater was used as an indicator of a high methodological quality of the study. “ 4/15-23 see major issues. 4/26 Please delete the word “by”. 4/30 “literature” should read ”estimate from the included study” or ”study” 4/43 “..pooled relative risks (RRs)..” should probably read “meta risks (RRmeta)…”. 4/47-52 please write the following items in this sentence in singular (not plural): heart disease; publication year; study quality score; race, gender; exposure assessment. (items not mentioned may remain in plural). 4/56 please write p-for-trend with a lower case p. 4/56. Did you not include fixed and random effects in the same model anywhere? As this reads, either fixed or random effects seem to be included in models. 5/4. Please give a reference supporting your choice to divide/multiply the open-range endpoint value by 1.2; and also explain the putative effect of this choice on your estimated meta effects in the discussion section. Results. 5/30 Supplemrntary should read supplementary. 5/31 “There are 3 studies addressed ischaemic heart disease incidence risk”. The sentence should probably read: There were 3 studies addressing risk of incident ischaemic heart disease.” 5/34 “Among the 20 studies that provided the heart disease risk estimates of silica exposure, 13 studies addressed the risk of ischaemic heart disease (including myocardial infarction and coronary heart disease) 9, 11-22; five studies reported the risk of pulmonary heart disease 8, 11, 12, 14, 17; three studies discussed the risk of other heart diseases 10, 12, 14” should better read: “Among the 20 studies that provided risk estimates for heart disease related to silica exposure, 13 studies addressed the risk of ischaemic heart disease (including myocardial infarction and coronary heart disease) 9, 11-22; five studies reported the risk of pulmonary heart disease 8, 11, 12, 14, 17; three studies discussed the risk of other heart diseases10, 12, 14” Please also consider to mention the relevant conditions included in other heart diseases. 5/39 “Most papers (n=7) published after 2010, three in the 2000s, and one in 1995.,” should read “Most of the included papers (n=7) were published after 2010,….”. The number of included papers do not add up to 20 – should they not? 5/48 “Results from overall risk estimate analysis revealed a positive association between silica exposure and all heart disease



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(Z = 4.06, P = 0.000), and we found an overall significantly increased risk of 10% (RR = 1.10, 95% CI = 1.05, 1.15)”. It seems unnecessary to explain the RR=1.10 by further specifying that this indicates a 10 % increase, if you agree, the sentence may be simplified into : “Results from overall risk estimate analysis revealed a positive association between silica exposure and all heart disease (RRmeta = 1.10, 95% CI = 1.05, 1.15)” 5/52-54. Please do not use capital letters starting the words pulmonary and ischaemic, unless after a full stop. 6/11 “Table 2 presents subgroup analyses, with estimates varying with categories of heart disease, reference groups…” should probably read “Table 2 presents subgroup analyses, showing the effects on estimates of association according to categories of heart disease, reference groups….” 6/11-15. Please see the comments to lines 4/47-52 and adjust accordingly. 6/38 now reads “We investigated the mortality linear association for pulmonary heart disease based on different silica exposure levels (P for testparm doses = 0.9627) (Supplementary Fig 1), and the pooled relative risk estimate revealed a significant increased risk to 1.39 (95% CI = 1.19, 1.62), indicating that risk of pulmonary heart disease among silica exposure populations might increase 39% per 1 mg/m3-years. However, there was a nonlinear association between silica exposure and ischaemic heart disease mortality (P for testparm doses = 0.000) (Supplementary Fig 2), and the pooled relative risk estimate dropped to 0.98 without significance (95% CI = 0.91, 1.05).” Please do not use a capital letter for p. Please use meta risk estimate, not pooled risk estimate. The last sentence is contradictory – if there was a nonlinear association, there should be a significant estimate. So, what you probably mean was that there was not a linear association between cumulated exposure to silica and ischaemic heart disease. If you state that the meta risk estimate dropped (like you do), please also state what was the original situation before the drop (do you here compare two situations, or do you describe the exposure-response analysis for IHD? Discussion. 6/50. “Through the systematic literature analysis,…” should read “Through this systematic review ,..” 6/53 “suggest positive association” should read “suggest positive associations” 6/54-56. Please state the results from exposure-response analysis in a separate sentence (as it now reads, you seemingly found associations only for pulmonary heart disease). 6/last – 7/1. A number of cohort studies based on different control analyses also indicated control groups play a potential role in silica exposure related heart disease risk estimate” should probably read “A number of cohort studies indicated that the selection of control groups in each primary study is a source of bias on estimating the association between silica exposure and heart disease” 7/2 “Our analyses showed that there was a significantly increased risk of heart disease when the external control was used as the reference group” should read “Our analyses showed that there was a significantly increased risk of heart disease when an external control group was used as reference”



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7/4-6 “In analyses of studies using total population reference groups, we found increased risks, but with no statistical significance.” Should read “In studies using the total population as reference, we found no statistically significant increase of risks.” 7/6-9 “That might be explicated by the “healthy worker effect”, which could cause the bias toward null in mortality studies with background populations as reference group” should probably read “This might possibly be explained by a healthy worker effect, which normally will cause a bias towards the null.” 7/9-14 “Analyses conducted on iron and/or steel foundry workers, mine and/or stone foundry, other unspecified workplaces workers showed modestly increased risks of heart disease. These results suggested that there might be some other minerals that should be taken into account to rule out the interaction on human health, such as occupational exposure to particulate matter”. Please do not use the “/” between and and or. The last part of the sentence makes no sense as occupational exposure to particulate matter includes both particulate matter from silica and other sources. It is well known that ultrafine particles may have other properties than the same minerals or element in courser particles. Is this what you meant? Could you perhaps have used information about particle size regarding crystalline silica in the primary studies to look into such differences? And particulate matters cannot be regarded as “other minerals” – they ARE the minerals of elements that they contain. 7/16 “..epidemiological studies had examined the relative risk of suffering from heart disease..” should read “epidemiological studies have examined the risk of heart disease…” 7/18. Please replace “high” with “increased” and SMR is not at rate, it is a ratio (please observe throughout text). 7/22-23. “The association between silica exposure and heart disease was stronger for adjusted smoking studies” should read “The association between silica exposure and heart disease was stronger for studies that were adjusted for smoking” 7/23-26 “Recently, silica-exposed workers who had at least 1 cigarette per day for at least 6 months were reported to have significantly increased hazard ration of ischaemic heart disease mortality (HR = 1.690, 95% CI = 1.083, 2.635)” . Should read “Recently, silica-exposed workers who had been smoking at least 1 cigarette per day for at least 6 months showed a significantly increased hazard ratio of ischaemic heart disease mortality (HR = 1.690, 95% CI = 1.083, 2.635) 7/27 publication years should read year of publication. “The” should read “A” 7/30 lager should read larger 7/31 indicated the increased risk should read showed increased risk 7/36 impact of silica should read impact of exposure to silica dust 7/44-45. “..exposure types of silica dust with asbestos, research categories of prospective cohort indicate significantly increased risk” should be explained better. You did not only find associations between silica dust with asbestos? What you mean is probably that the significantly increased RRmeta that you produced was stable across different exposure assessments strategies and combinations with other exposures than silica dust 7/47. Please replace “the” with “an”



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7/48. Please replace “..but no excess risk evidence was found..” with “..but not for..” 7/50-52 “The possible reason for the different results probably was that there were more deaths resulted from the competing heart diseases or preceding respiratory disease.” Is really not intelligible for this reviewer. You study mortality from heart diseases. Then heart diseases clearly cannot compete with this outcome. Do you mean that, regarding the difference between pulmonary and ischaemic heart disease, there is a higher likelihood that preceding (or also caused by the exposure?) respiratory disease is a competing cause of death to a higher degree for ischaemic heart disease? I think this would be more in line with your reference to Koskela in the next sentence. 7/59-60 Please replace “These evidences” with “This evidence” and “occupational silica exposure” with “occupational exposure to silica dust” 8/2. Please replace “..results in an increased risk of heart disease are not well explored” with “..could possibly increase the risk of heart disease are not well understood” 8/4 Please replace dusts with dust 8/6-7 “..Some of other related studies showed that...” should read “It has also been shown that…” 8/12-13 “The major strength was that we used comprehensive and robust search strategy without..” should read “ A major strength of the present study is the comprehensive and robust search strategy without…” 8/15 “On the other hand,..” would mean that the following was not a strength. So, I suggest what will cover what the authors mean is “Further strengths were the sensitivity analysis, subgroup analyses, meta-regression analyses, and exposure-response analyses that were performed.” 8/18-23 “Major limitations were that the different characteristics of included literatures leaded to significantly high heterogeneity, two studies that reported incidence risk rather than mortality risk of heart disease were included, studies included for exposure-response analyses were few.” I am not sure that including two studies of incident heart disease is a limitation. Could this sentence suggestedly be changed to: “Major limitations were the high heterogeneity between studies, precluding to some degree firm conclusions” ?, and thereafter: “There were few studies included for exposure-response analyses. 8/29-30. “Confirmation of this positive association may have important occupational health implications on primary prevention strategies for heart disease”. I am not so sure of this, since exposure to silica dust not very prevalent in the population. It would be more warranted to say: “Confirmation of this positive association may have important occupational health implications on primary prevention strategies for diseases related to exposure to silica dust”. 8/52-54: “…also supported by Occupational health risk assessment and national occupational health standard setting project (131031109000150003).” Should read “also supported by the Occupational health risk assessment and national occupational health standard setting project (131031109000150003).” Please add information about who are providing the financial support for the last source. Table 1.



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13/26. The risk estimate and/or confidence interval is wrong for the first estimate of Chen et al (1.05 (1.04-1.33)) 14/36 footnote to Table 1. “: If one paper provides SMR and RR values, RR included in priority” should probably read “: If a paper provides both SMR and RR values, the RR value is presented” Table 2. 15/4-5. The column R value for pooled RR can be deleted, as it can be deducted from the confidence limit of the RR which of them are statistically significant. I also suggested to drop the column beta (95%) of regression meta-regression analysis, as it seems arbitrary what are the reference categories for this analysis, and further, this adds little to the understanding of the literature. Also, I have suggested elsewhere not to use the expression “pooled” for the meta-analysis that you did perform in this study. I.e. use meta-RR instead of pooled RR. 16/39-40. Footnote. It now reads” a: All heart disease is the index of original index; b: other heart diseases include Hypertensive heart disease, etc because anyone of them is referred to in one article or one cohort study; c: the exact 95 % CI range is 1.003 to 1.146; -:excluded for that there are unspecified data or only one article; d: the exact β is -0.000863; *: P<0.05.” a. What do you mean by index of the original index? Is it not the conditions that follow from the inclusion criteria. b. Do not use “etc”, the explanation of other heart disease as “because anyone of them is referred to in one article or one cohort study” is ambiguous, please consider if this explanation is necessary, and, if so, give the information that is needed to comprehend what you included as “other heart disease”. c. The exact 95% CI is 1.003 to 1.146. What CI do you refer to here? I am not able to see where the c superscript is. d. You have a d superscript in line page/line 15/10 that is explained after “-“ in the footnote, it would be easier to read if all letters of superscript are explained in sequence. The d footnote is possible to misunderstand, since the use of exact can be interpreted to stem from an exact test, which probably was not the case. I suggest you drop footnote d. In the same footnote, you state: “-:excluded for that there are unspecified data or only one article”. Did you mean: “-:excluded due to lack of data or only one article giving an estimate”? In the footnotes to Table 2, continued (next two pages), you have a different explanation of the footnotes than in the first page of Table 2, this probably should be identical for all three pages of Table 2.


Reviewer(s)' Comments to Author:

Reviewer: 2


1. Page 4/line 15-23. As this reads now, 4 authors independently read and scored articles, and

disagreements were solved by involving a third person. This does not make sense. Also the sentence

“…From studying to using a piloted data collection form,…” does not make sense. Do you mean “Four

authors participated in the scoring of articles. Two authors independently read and scored each



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article, filling in information in a piloted data collection form. Disagreements were solved by

discussions with a third author”? Or was the scoring performed by 4 authors, with a 5th person as an

adjudicator (was this 5th person also one of the authors?).


Thank you for your comment. We revised these two points in “Study and data collection processes”

section to make it clear.

Revised version: “Four of the authors (Kai Liu, Meng Ye, Min Mu and Weijiang Hu) designed this

study; Meng Ye and Weijiang Hu assessed exclusion and inclusion criteria for full-text articles. All

reviewers independently reviewed titles and abstracts of all identified citations, filling in information in

a piloted data collection form. Disagreements were resolved by discussion and consensus, with Min

Mu as an adjudicator.”


2. P 5/l 18-25. The sentence reading “101 studies’ population weren’t occupational exposure to silica,

50 were repetitive research results, 25 Occupational exposure not specified in protocol (ie: Koskela.

Etc,34 the level of low (< 20 mg/m3) means for non-exposed population?) and 27 other studies were

excluded because the risk of exposed group was calculated by the populations of the silicosis instead

of occupational silica-exposed populations.” Is hard to read, and probably include several imprecise

items.

I have several objections to this section:

Firstly, did you mean: “We excluded 101 studies that did not include occupational exposure to silica..”

? “50 studies were repetitive research results” needs further explanation – do you mean results were

published in several articles, and only the original publication was included? “25 Occupational

exposure not specified in protocol (ie: Koskela. Etc,”. Here it is not possible to sort out what you really

mean. The abbreviation i.e. (that is) seems misplaced – did you mean e.g. (for example)?, and the

“etc” must be removed here. What is the difference between the 101 studies not including

occupational exposure to silica and the mentioned 25 studies here? “34 the level of low (< 20 mg/m3)

means for non-exposed population?) and 27 other studies were excluded because the risk of exposed

group was calculated by the populations of the silicosis instead of occupational silica-exposed

populations.” The first part of this needs explanation. 20 mg/m3 must be considered an

overwhelmingly high exposure If it refers to respirable crystalline silica, and do not indicate a non-

exposed population – or did you mean non-occupationally exposed population (and thus probably 20

micrograms per cube?)?


Thank you for your comment. We revised these five points in “Overview of studies included in the

systematic review” section.

Firstly, we excluded 101 studies that didn’t include occupational exposure to silica. Secondly, 50

studies were excluded for repetitive research results which were published in several articles. Thirdly,

we removed “etc” and replaced “i.e.” by “e.g.”. Fourthly, The relationship between 101 studies and 25

studies was independent. Fifthly, data of Koskela R S, et al (2005) were unclear: (1) this study didn’t

define the level of low dust < 20 mg/m3 as occupational silica exposure > 0 mg/m3, and there was no

other obvious evidence; (2) the study population was only derived from six cohorts variously exposed

to dust; (3) the morbidity was assessed by “age adjusted incidence rates per 100 000 person-years”;

(4) there were no confidence intervals and couldn’t be calculated.




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6/5-8. Now reads: “Sensitivity analysis indicated that eleven studies were the main origin of

heterogeneity.10-13, 16, 20, 21, 23-27 The heterogeneity decreased after the exclusion of these five

data (I2 = 41.9%). However, the corresponding pooled relative risk estimate still kept significant (RR =

1.14, 95% CI = 1.10, 1.18).” Please clarify what you mean here ; if eleven studies were the main

origin of heterogeneity, what is the intellectual link to the next sentence describing that excluding five

data (do you mean studies?), and not after excluding all eleven studies from the meta analysis of

sensitivity. Please, also give the estimate of heterogeneity both before and after exclusion of the

relevant studies of main origin to heterogeneity, and not only I squared after exclusion. In the last

sentence (6/8), to me it would be better to say that the meta risk estimate (not pooled estimate)

remained significant after exclusion of the studies that were the main origin of heterogeneity between

studies. If it is the meta regression that is presented in the full data set, it seems misplaced (why put

this under a heading of Subgroup analysis?). If it is the comparison between estimated coefficients of

regression between silica exposure and different types of outcome, to me this seems to add little to

the presentation (“how much more significant is one outcome compared to another outcome hardly

adds substantially to the information obtained by the study). Also, describing this as two situations

adds to the confusion that I feel about this. Seemingly, like in table 2 you are dealing with additive

relative risk values here, and this should be explained for clarity. The point described under “situation

(2)” could be of interest, but needs a clearer presentation to be intelligible. The last part of the section

stating: “(2) Coefficient of study quality assessment score 7 VS 6 was -0.28 (95% CI = -0.54, -0.03, P

= 0.033), which indicated that the greater the proportion of heart disease in cohort studies of low

quality score, the higher pooled RR for low quality score cohort studies compared with heart disease

(Table 2).” also needs improvement – it is not possible to follow the intellectual content here. The

indicator of study quality is suggestedly not a coefficient, but the difference between studies scored

with quality =7 vs quality=6 is interesting to know. Also; the statement that the greater the proportion

of heart disease …. The higher pooled RR (meta RR).. is not very surprising.

If you want to say something about differences according to study quality, perhaps you can say”

Comparing studies with quality score=7 to quality score=6, we found that the studies of higher quality

had a lower estimate of effect from silica exposure, and give the estimates of the effects. But, would it

not be more easy to read if you kept the estimates here on a ratio level, and gave the RRmeta of

studies obtaining a quality score of 7 compared to the RRmeta of studies obtaining 6?


Thank you for your comment and suggestion. We revised these four

points in “Sensitivity analysis” and “Subgroup analyses and meta-regression analyses”

sections respectively.

Revised “Sensitivity analysis” section: Sensitivity analysis indicated that twelve studies were the main

origin of heterogeneity (Coronary heart disease mortality data from Dong D, et al. (1995) weren’t

excluded),10-13, 16, 20, 21, 23-27 the heterogeneity decreased significantly (before exclusion: I2 =

94.9%, P = 0.000; after exclusion: I2 = 41.9%, P = 0.078) and the meta risk estimate remained

significant (RR = 1.14, 95% CI = 1.10, 1.18; P = 0.000) after exclusion of the studies that were the

main origin of heterogeneity between studies.

We dropped the column beta (95%) of regression meta-regression analysis.


6/16-28. In the description of the results from meta-regression analysis, it is hard to follow the

meaning of this last section. Therefore, this reviewer is not able to suggest a sound presentation of

what the authors have done and observed.




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Thank you for your comment. We dropped the column beta (95%) of regression meta-regression

analysis.


Table 2.

15/4. Heading “I2 Value (%)” should read “I2 value (%)”, “P Value for Heterogeneity” should read “p

value for heterogeneity”, “Pooled RR” should better read “Meta RR”, “P-Value for Pooled RR” should

read “p value for meta RR”. The rationale for the column to the right, named beta of regression metat-

regression analysis seems unclear to this reviewer. Is the idea that “other heart disease with beta

=1.00 is not affected by silica exposure and the other outcomes are related to that “reference”. If you

wish to keep this column in the table, it need a good description with rationale in the methods chapter

as well as an interpretation in the discussion. Seemingly, the chosen strategy for analysis here only

identified differences between ischaemic heart disease and other heart disease (if I understand the

table right). To me, it seems a better strategy to delete this column.


Thank you for your comment. We revised these points in table 2 and other related sections, and we

deleted the column beta (95%) of regression meta-regression analysis.


Abstract. Some sentences can be simplified. E.g. p 1/l 47 “In this meta-analysis, the overall risk of

heart disease was found increased (10%) significantly among silica-exposed workers (pooled RR =

1.10, 95% CI = 1.05, 1.15)” should read “ In this meta analysis, we identified an overall risk of heart

disease (pooled RR=1.10, 95 % CI 1.05, 1.15)”. Also, there is no need to repeat that the study is a

systematic review with meta analysis several times during the abstract.

2/27 Heading Intrduction should read Introduction.

2/32 reclassified should read classified.

2/35 the use of the expression “workers’ negligence of self protection” to my opinion places too much

responsibility on the worker – for instance: are the authors sure that the need to use protective means

are understood, are the equipment compatible with the workplace and the need to consume the

needed extra time that will unevitably be connected with the use of personal protection; included the

slowing of work implying physical exertion? If not so, I suggest a more balanced view of why workers

do not use relevant personal protection equipment when working in dusty environments, eventually if

you withheld the contention about worker’ negligence, it shoud be supported by relevant references

about whether suboptimal use of PPE should be ascribed to workers “negligence”.

2/44 “silica-exposed diseases” should read “ diseases at increased risk due to silica exposure”. 2/48

“Nevertheless, the link between silica exposure and the relative risk of heart disease mortality ...”

Should read …”Nevertheless, the link between silica exposure and heart disease mortality….”

2/ 53&59. I prefer that “researches” reads “research”.


Thank you for your suggestion. We revised these points in “Abstract” section and deleted “workers’

negligence of self protection” expression.




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Methods.

3/34 “The exposure of interest was silica-exposed populations..” should read “The exposure of

interest was silica dust. We included studies of silica-related occupation….”

3/38 - 44 Please do not use capital letters unless after full stop, except TCE, JEM, and SD). 3/54

“Furthermore, we excluded cases combing with pneumoconiosis or silicosis as much as possible”

should probably read “Furthermore, we excluded cases of heart disease combining with

pneumoconiosis or silicosis when this was possible to infer from information in the primary study”.

This para also leaves a question about how cases could be excluded (did you exclude studies where

a diagnostic group combining pneumoconiosis or silicosis with heart disease was used? Cases could

not be excluded on a case-to-case basis since this was a meta-analysis? 3/58 in line with the latter

comment: “That’s to say, we only included the cases of nonsilicotics and underlying death cause in

two of these included literatures respectively”. Is this a specification of the former paragraph? You

cannot include the “cases of nonsilicotics and underlying death cause..” – this has no intelligible

interpretation. Please look closely into the meaning of the paragraphs from 3/54 on.

4/2 ..”about” should probably read “for”.

4/10 “Giving each satisfactory answer could receive one or two point, only high methodological quality

articles were considered if the article was with a score of six or more.” Should probably read “We

scored each study with zero, one, or two point for each item, the sum of scores for each study was

used to classify the quality of the study, and a score of six or greater was used as an indicator of a

high methodological quality of the study. “ 4/15-23 see major issues.

4/26 Please delete the word “by”.

4/30 “literature” should read ”estimate from the included study” or ”study”

4/43 “..pooled relative risks (RRs)..” should probably read “meta risks (RRmeta)…”.

4/47-52 please write the following items in this sentence in singular (not plural): heart disease;

publication year; study quality score; race, gender; exposure assessment. (items not mentioned may

remain in plural).

4/56 please write p-for-trend with a lower case p.

4/56. Did you not include fixed and random effects in the same model anywhere? As this reads, either

fixed or random effects seem to be included in models.

5/4. Please give a reference supporting your choice to divide/multiply the open-range endpoint value

by 1.2; and also explain the putative effect of this choice on your estimated meta effects in the

discussion section.


Thank you for your suggestion. We revised these points in “Methods” section.

Response to comment on 3/54: there was one study that reported SRR values for selected causes of

death by silicosis status (Dong D, et al. (1995)), and we included SRR based on total cases.

Response to comment on 4/56: we conducted exposure-response analyses for ischaemic heart

disease and pulmonary heart disease with linear association analysis (including two-stage fixed-

effects) or nonlinear association analysis (including random-effects), which was determined by

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stage fixed effects dose-response model was included for pulmonary heart disease, while two-stage

random-effects dose-response model was included for ischaemic heart disease.

Response to comment on 5/4: we gave a reference supporting our choice to divide/multiply the open-

range endpoint value by 1.2, and also explained the putative effect of this choice on estimated meta

effects in the discussion section.


Results.

5/30 Supplemrntary should read supplementary.

5/31 “There are 3 studies addressed ischaemic heart disease incidence risk”. The sentence should

probably read: There were 3 studies addressing risk of incident ischaemic heart disease.”

5/34 “Among the 20 studies that provided the heart disease risk estimates of silica exposure, 13

studies addressed the risk of ischaemic heart disease (including myocardial infarction and coronary

heart disease) 9, 11-22; five studies reported the risk of pulmonary heart disease 8, 11, 12, 14, 17;

three studies discussed the risk of other heart diseases 10, 12, 14” should better read: “Among the 20

studies that provided risk estimates for heart disease related to silica exposure, 13 studies addressed

the risk of ischaemic heart disease (including myocardial infarction and coronary heart disease) 9, 11-

22; five studies reported the risk of pulmonary heart disease 8, 11, 12, 14, 17; three studies discussed

the risk of other heart diseases10, 12, 14” Please also consider to mention the relevant conditions

included in other heart diseases.

5/39 “Most papers (n=7) published after 2010, three in the 2000s, and one in 1995.,” should read

“Most of the included papers (n=7) were published after 2010,….”. The number of included papers do

not add up to 20 – should they not?

5/48 “Results from overall risk estimate analysis revealed a positive association between silica

exposure and all heart disease (Z = 4.06, P = 0.000), and we found an overall significantly increased

risk of 10% (RR = 1.10, 95% CI = 1.05, 1.15)”. It seems unnecessary to explain the RR=1.10 by

further specifying that this indicates a 10 % increase, if you agree, the sentence may be simplified into

: “Results from overall risk estimate analysis revealed a positive association between silica exposure

and all heart disease (RRmeta = 1.10, 95% CI = 1.05, 1.15)”

5/52-54. Please do not use capital letters starting the words pulmonary and ischaemic, unless after a

full stop.

6/11 “Table 2 presents subgroup analyses, with estimates varying with categories of heart disease,

reference groups…” should probably read “Table 2 presents subgroup analyses, showing the effects

on estimates of association according to categories of heart disease, reference groups….” 6/11-15.

Please see the comments to lines 4/47-52 and adjust accordingly.

6/38 now reads “We investigated the mortality linear association for pulmonary heart disease based

on different silica exposure levels (P for testparm doses = 0.9627) (Supplementary Fig 1), and the

pooled relative risk estimate revealed a significant increased risk to 1.39 (95% CI = 1.19, 1.62),

indicating that risk of pulmonary heart disease among silica exposure populations might increase 39%

per 1 mg/m3-years. However, there was a nonlinear association between silica exposure and

ischaemic heart disease mortality (P for testparm doses = 0.000) (Supplementary Fig 2), and the

pooled relative risk estimate dropped to 0.98 without significance (95% CI = 0.91, 1.05).” Please do

not use a capital letter for p. Please use meta risk estimate, not pooled risk estimate. The last

sentence is contradictory – if there was a nonlinear association, there should be a significant

estimate. So, what you probably mean was that there was not a linear association between cumulated



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exposure to silica and ischaemic heart disease. If you state that the meta risk estimate dropped (like

you do), please also state what was the original situation before the drop (do you here compare two

situations, or do you describe the exposure-response analysis for IHD?


Thank you for you suggestion and comment. We revised these points in “Methods” section.

Response to comment on 5/39: we deleted that expression, and the number of included papers was

20.

Response to comment on 6/38: our exposure-response analyses for ischaemic heart disease

revealed p for testparm doses = 0.000, which indicated that there was a nonlinear association

between silica exposure and ischaemic heart disease. But the meta relative risk estimate of ischaemic

heart disease mortality dropped to 0.98 without significance (95% CI = 0.91, 1.05) comparing to the

overall heart disease risk estimate (meta RR = 1.10).


Discussion.

6/50. “Through the systematic literature analysis,…” should read “Through this systematic review ,..”

6/53 “suggest positive association” should read “suggest positive associations”

6/54-56. Please state the results from exposure-response analysis in a separate sentence (as it now

reads, you seemingly found associations only for pulmonary heart disease).

6/last – 7/1. A number of cohort studies based on different control analyses also indicated control

groups play a potential role in silica exposure related heart disease risk estimate” should probably

read “A number of cohort studies indicated that the selection of control groups in each primary study

is a source of bias on estimating the association between silica exposure and heart disease” 7/2 “Our

analyses showed that there was a significantly increased risk of heart disease when the external

control was used as the reference group” should read “Our analyses showed that there was a

significantly increased risk of heart disease when an external control group was used as reference”

7/4-6 “In analyses of studies using total population reference groups, we found increased risks, but

with no statistical significance.” Should read “In studies using the total population as reference, we

found no statistically significant increase of risks.”

7/6-9 “That might be explicated by the “healthy worker effect”, which could cause the bias toward null

in mortality studies with background populations as reference group” should probably read “This might

possibly be explained by a healthy worker effect, which normally will cause a bias towards the null.”

7/9-14 “Analyses conducted on iron and/or steel foundry workers, mine and/or stone foundry, other

unspecified workplaces workers showed modestly increased risks of heart disease. These results

suggested that there might be some other minerals that should be taken into account to rule out the

interaction on human health, such as occupational exposure to particulate matter”. Please do not use

the “/” between and and or. The last part of the sentence makes no sense as occupational exposure

to particulate matter includes both particulate matter from silica and other sources. It is well known

that ultrafine particles may have other properties than the same minerals or element in courser

particles. Is this what you meant? Could you perhaps have used information about particle size

regarding crystalline silica in the primary studies to look into such differences? And particulate matters

cannot be regarded as “other minerals” – they ARE the minerals of elements that they contain.



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7/16 “..epidemiological studies had examined the relative risk of suffering from heart disease..” should

read “epidemiological studies have examined the risk of heart disease…”

7/18. Please replace “high” with “increased” and SMR is not at rate, it is a ratio (please observe

throughout text).

7/22-23. “The association between silica exposure and heart disease was stronger for adjusted

smoking studies” should read “The association between silica exposure and heart disease was

stronger for studies that were adjusted for smoking”

7/23-26 “Recently, silica-exposed workers who had at least 1 cigarette per day for at least 6 months

were reported to have significantly increased hazard ration of ischaemic heart disease mortality (HR =

1.690, 95% CI = 1.083, 2.635)” . Should read “Recently, silica-exposed workers who had been

smoking at least 1 cigarette per day for at least 6 months showed a significantly increased hazard

ratio of ischaemic heart disease mortality (HR = 1.690, 95% CI = 1.083, 2.635)

7/27 publication years should read year of publication. “The” should read “A”

7/30 lager should read larger

7/31 indicated the increased risk should read showed increased risk

7/36 impact of silica should read impact of exposure to silica dust

7/44-45. “..exposure types of silica dust with asbestos, research categories of prospective cohort

indicate significantly increased risk” should be explained better. You did not only find associations

between silica dust with asbestos? What you mean is probably that the significantly increased

RRmeta that you produced was stable across different exposure assessments strategies and

combinations with other exposures than silica dust

7/47. Please replace “the” with “an”

7/48. Please replace “..but no excess risk evidence was found..” with “..but not for..”

7/50-52 “The possible reason for the different results probably was that there were more deaths

resulted from the competing heart diseases or preceding respiratory disease.” Is really not intelligible

for this reviewer. You study mortality from heart diseases. Then heart diseases clearly cannot

compete with this outcome. Do you mean that, regarding the difference between pulmonary and

ischaemic heart disease, there is a higher likelihood that preceding (or also caused by the exposure?)

respiratory disease is a competing cause of death to a higher degree for ischaemic heart disease? I

think this would be more in line with your reference to Koskela in the next sentence.

7/59-60 Please replace “These evidences” with “This evidence” and “occupational silica exposure”

with “occupational exposure to silica dust”

8/2. Please replace “..results in an increased risk of heart disease are not well explored” with

“..could possibly increase the risk of heart disease are not well understood”

8/4 Please replace dusts with dust

8/6-7 “..Some of other related studies showed that...” should read “It has also been shown that…”

8/12-13 “The major strength was that we used comprehensive and robust search strategy without..”

should read “ A major strength of the present study is the comprehensive and robust search strategy

without…”



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8/15 “On the other hand,..” would mean that the following was not a strength. So, I suggest what will

cover what the authors mean is “Further strengths were the sensitivity analysis, subgroup analyses,

meta-regression analyses, and exposure-response analyses that were performed.” 8/18-23 “Major

limitations were that the different characteristics of included literatures leaded to significantly high

heterogeneity, two studies that reported incidence risk rather than mortality risk of heart disease were

included, studies included for exposure-response analyses were few.” I am not sure that including two

studies of incident heart disease is a limitation.

Could this sentence suggestedly be changed to: “Major limitations were the high heterogeneity

between studies, precluding to some degree firm conclusions” ?, and thereafter: “There were few

studies included for exposure-response analyses.

8/29-30. “Confirmation of this positive association may have important occupational health

implications on primary prevention strategies for heart disease”. I am not so sure of this, since

exposure to silica dust not very prevalent in the population. It would be more warranted to say:

“Confirmation of this positive association may have important occupational health implications on

primary prevention strategies for diseases related to exposure to silica dust”.

8/52-54: “…also supported by Occupational health risk assessment and national occupational health

standard setting project (131031109000150003).” Should read “also supported by the Occupational

health risk assessment and national occupational health standard setting project

(131031109000150003).” Please add information about who are providing the financial support for the

last source.


Thank you for your comment and suggestion. We revised these points in “DISCUSSION”, “Strengths

and limitations” and “Funding” sections.


Table 1.

13/26. The risk estimate and/or confidence interval is wrong for the first estimate of Chen et al (1.05

(1.04-1.33))

14/36 footnote to Table 1. “: If one paper provides SMR and RR values, RR included in priority”

should probably read “: If a paper provides both SMR and RR values, the RR value is presented”

Table 2.

15/4-5. The column R value for pooled RR can be deleted, as it can be deducted from the confidence

limit of the RR which of them are statistically significant. I also suggested to drop the column beta

(95%) of regression meta-regression analysis, as it seems arbitrary what are the reference categories

for this analysis, and further, this adds little to the understanding of the literature. Also, I have

suggested elsewhere not to use the expression “pooled” for the meta-analysis that you did perform in

this study. I.e. use meta-RR instead of pooled RR. 16/39-40. Footnote. It now reads” a: All heart

disease is the index of original index; b: other heart diseases include Hypertensive heart disease, etc

because anyone of them is referred to in one article or one cohort study; c: the exact 95 % CI range is

1.003 to 1.146; -:excluded for that there are unspecified data or only one article; d: the exact β is -

0.000863; *: P<0.05.”

a. What do you mean by index of the original index? Is it not the conditions that follow from the

inclusion criteria.



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b. Do not use “etc”, the explanation of other heart disease as “because anyone of them is

referred to in one article or one cohort study” is ambiguous, please consider if this explanation is

necessary, and, if so, give the information that is needed to comprehend what you included as “other

heart disease”.

c. The exact 95% CI is 1.003 to 1.146. What CI do you refer to here? I am not able to see where

the c superscript is.

d. You have a d superscript in line page/line 15/10 that is explained after “-“ in the footnote, it

would be easier to read if all letters of superscript are explained in sequence. The d footnote is

possible to misunderstand, since the use of exact can be interpreted to stem from an exact test, which

probably was not the case. I suggest you drop footnote d.

In the same footnote, you state: “-:excluded for that there are unspecified data or only one article”. Did

you mean: “-:excluded due to lack of data or only one article giving an estimate”? In the footnotes to

Table 2, continued (next two pages), you have a different explanation of the footnotes than in the first

page of Table 2, this probably should be identical for all three pages of Table 2.


Thank you for your comment and suggestion. We revised these points in table 1 and table 2.

Response to comment on table 1 13/26: we made mistake in table 1 by copying wrong confidence

interval (1.04-1.33) for the first estimate (1.050 (1.044, 1.056)) of Chen W, et al. (2012), but risk

estimate and confidence interval were right in our database (1.05 (1.04, 1.06)).

Furthermore, we have checked through our manuscript to ensure materials are complete.

Response to comment on table 2 16/39-40:

a: because there were 5 articles that just reported “All heart disease” without detailed data for the

categories of heart disease, our main outcome included “pulmonary heart disease”,8, 11, 12, 14, 17

“ischaemic heart disease” (including myocardial infarction and coronary heart disease),9, 11-23 “other

heart diseases” (including hypertensive heart disease, chronic rheumatic heart disease),12, 14 and

“all heart disease (including cardiovascular disease)”.10, 19, 20, 26, 27.

b: other heart diseases include hypertensive heart disease and chronic rheumatic heart disease.

c: we dropped the column beta (95%) of regression meta-regression analysis and c superscript.

d: we dropped the column beta (95%) of regression meta-regression analysis and d superscript.

VERSION 3 - REVIEW


National Institute of Occupational Health

REVIEW RETURNED 08-Sep-2019

GENERAL COMMENTS The manuscript now has been revised two times. Still the manuscript has not been subjected to a review of the language performed by a native English speaking person with knowledge in the area, although I have indicated this as a prerequisite to obtain a manuscript that is acceptable. I would advice not to publish the paper unless the English language issue is solved. Please acknowledge that this is not only about using the right



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expressions, but also to find clear expressions stating what the authors mean and have found. The manuscript in this respect still has a lot of unclear statements and explanations. Please also see my last comprehensive reviewer comments – many of them are not solved properly in revision 2. An example is the first sentence of the introduction: “Silica is a kind of common mineral composition in sand, rock and soil”. What is of interest regarding risk of heart disease connected with exposure to silica, is respirable (or possibly also to some degree, inhalable) silica dust – and this relates to more than the mineral composition of the material for exposure to take place. As the second revision now reads, the authors use a lot of parentheses. These should be replaced to a large degree by full sentences. Below, I include some examples and also some new major issues with revision 2 – please observe that it is not sufficient to solve those problems in order to obtain a manuscript that is suited for publication. Some information has been lost during the second revision. E.g. the three first sentences in the abstract – as the associations in the third sentence expands the information in the second, they cannot be described as similar associations to the main association – the associations of pulmonary disease and ischaemic heart disease are the true explanations of the association of total heart disease, and the content of the parenthesis to the third sentence, describing “(categories of heart disease risk estimate…)”, is not possible to understand. These sentences should also state that the authors found an increase of overall risk of heart disease. The period of inclusion of primary articles for the review is still missing in the methods (only found in Table 1), and should be reported in the methods section. How was it possible for the authors to expand the period of inclusion until June 2019, while revising the manuscript (reference 44 included from the first revision on is dated June 2019)? Does this mean that a new and complete search was processed while revising the manuscript. Or is the search not complete for the whole period? The description of the study and data collection process in revision 2 does not include other than the screening – so the selection of papers to be included must be described in detail including how quality of the articles including potential for bias was assessed and scored. The introduction in revision 2 of the explanation of the substitution of open-ended intervals by the given bound multiplied with or divided with 1.2, with reference to the new reference 34 (Greenland and Longnecker 1994), is very problematic and must be reviewed by a statistician. This reviewer cannot find a justification for the choice of dividing/multiplying open bounds with 1.2 to obtain the interval in reference 34. The statistics of the meta-analysis itself, though, seems OK.


Reviewer(s)' Comments to Author:


The manuscript now has been revised two times. Still the manuscript has not been subjected to a

review of the language performed by a native English speaking person with knowledge in the area,

although I have indicated this as a prerequisite to obtain a manuscript that is acceptable. I would



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advice not to publish the paper unless the English language issue is solved. Please acknowledge that

this is not only about using the right expressions, but also to find clear expressions stating what the

authors mean and have found. The manuscript in this respect still has a lot of unclear statements and

explanations.


Thank you for your suggestion. We tried to improve our English quality and revised unclear

sentences, grammatical errors and wrong use of prepositions. Such as we revised “researches” of

introduction section as “research”, revised capital letters unless after full stop, revised “study quality

scores” as “study quality score”, stated the results from exposure-response analysis in a separate

sentence, deleted the “/” between and and or, replaced “high SMR” with “increased SMR” and revised

the “publication years” as “year of publication”.


Please also see my last comprehensive reviewer comments – many of them are not solved properly

in revision 2.


Thank you for your comment. We carefully revised our manuscript according to your comprehensive

reviewer comments on revision one and two.


An example is the first sentence of the introduction: “Silica is a kind of common mineral composition in

sand, rock and soil”. What is of interest regarding risk of heart disease connected with exposure to

silica, is respirable (or possibly also to some degree, inhalable) silica dust – and this relates to more

than the mineral composition of the material for exposure to take place. Authors’Response 3

Thank you for your comment and suggestion. We improved article structure in introduction part, and

we revised previous first sentence of the introduction section as “Silica is the key ingredient of dust,

with widespread exposure in working environment” to make introduction part fluent.


As the second revision now reads, the authors use a lot of parentheses. These should be replaced to

a large degree by full sentences.


Thank you for your comment. We replaced many parentheses by full sentences such as we revised

“And the similar positive association was obvious in pulmonary heart disease (categories of heart

disease risk estimate: meta RR = 1.24, 95% CI = 1.08, 1.43; exposure-response analysis: meta RR =

1.39, 95% CI = 1.19, 1.62).” as “Stronger evidences of association with pulmonary heart disease were

found through both categories of heart disease risk estimate (meta-RR = 1.24, 95% CI = 1.08,

1.43) and exposure-response analyses (meta-RR = 1.39, 95% CI = 1.19, 1.62)..” in abstract section.


The three first sentences in the abstract – as the associations in the third sentence expands the

information in the second, they cannot be described as similar associations to the main association –

the associations of pulmonary disease and ischaemic heart disease are the true explanations of the

association of total heart disease, and the content of the parenthesis to the third sentence, describing



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“(categories of heart disease risk estimate…)”, is not possible to understand. These sentences should

also state that the authors found an increase of overall risk of heart disease.


Thank you for your comment. We revised these points in abstract section: “Results suggest a

significant increase of overall heart disease risk (meta-RR = 1.08, 95% CI = 1.03, 1.13). Stronger

evidences of association with pulmonary heart disease were found through both categories of heart

disease risk estimate (meta-RR = 1.24, 95% CI = 1.08, 1.43) and exposure-response analyses (meta-

RR = 1.39, 95% CI = 1.19, 1.62).”.


The period of inclusion of primary articles for the review is still missing in the methods (only found in

Table 1), and should be reported in the methods section.


Thank you for your suggestion. We reported the period of inclusion in “Data sources-Abstract” section

and “Search strategy-Methods” section.


How was it possible for the authors to expand the period of inclusion until June 2019, while revising

the manuscript (reference 44 included from the first revision on is dated June 2019)? Does this mean

that a new and complete search was processed while revising the manuscript. Or is the search not

complete for the whole period?


Thank you for your comment. Because there were seven months since we carried out a literature

search in December 2018, we expanded the period of inclusion until June 2019 to find whether there

were new published related articles or not.


The description of the study and data collection process in revision 2 does not include other than the

screening – so the selection of papers to be included must be described in detail including how quality

of the articles including potential for bias was assessed and scored.


Thank you for you suggestion and comment. We added detailed processes about study and data

collection process: “two reviewers (Kai Liu and Min Mu) extracted study characteristics, outcomes and

study quality data, filling information in a piloted data collection form. Only high methodological quality

studies with a score of six or higher were included.”. Moreover, The Newcastle-Ottawa Quality

assessment Scale for cohort studies was used for quality assessment.


The introduction in revision 2 of the explanation of the substitution of open-ended intervals by the

given bound multiplied with or divided with 1.2, with reference to the new reference 34 (Greenland

and Longnecker 1994), is very problematic and must be reviewed by a statistician. This reviewer

cannot find a justification for the choice of dividing/multiplying open bounds with

1.2 to obtain the interval in reference 34.



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Thank you for your comment and suggestion. We replaced our reference 34 with a appropriate

reference (Longnecker M P et al. 1988): “Midpoints of consumption categories were used for dose-

response calculations. For open-ended, high-Intake categories, the midpoint of the category was

estimated to be 20% greater than the lower boundary specified by the original authors.”

The previous reference (Greenland and Longnecker 1994) was cited because its substitution of open-

ended intervals (“Assigned dose”) was calculated by the given bound (“Alcohol”) multiplied with or

divided with 1.2. (Table 1, page 1302) Thank you very much.



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Documents

PEER REVIEW HISTORY ...association with cor pulmonale! A study of cardiovascular mortality (both cor pulmonale and IHD) from 2015 (Kreuzer et al) has not been included in the Chinese