Supplemental Results

1

SUPPLEMENTAL RESULTS

Selection of Studies

Supplemental Figure 1 presents the successive steps during the selection process of eligible studies. From the 767 articles rendered from the algorithm-based search, 652 were deemed irrelevant according to their respective title or abstract. The full text of the of the remaining 115 articles was evaluated, whereas 47 additional articles were considered potentially eligible through the “snowball” process and were therefore retrieved and evaluated in full text. Of the 158 aforementioned articles, 145 met the eligibility criteria, whereas 17 articles [1-17] were excluded due for to various eligibilityspecific reasons, as presented in the Supplementary Table 1. Moreover, the updated NARECHEM data [18] for the period 1996-2013 were provided by the primary investigator, yielding a grand total of 146 eligible studies.

Regarding issues pertaining to overlapping studies, the sets of studies excluded due to this reason are presented by country in alphabetical order, given the substantial amount of mutually overlapping literature.

Two Australian studies [19,20] were excluded due to overlap with the study by Milne et al. (2010) [21]. Moreover, only the paternal arm was retained from another eligible article by Milne et al. [22]; the maternal arm of the latter article was excluded from our study due to overlap with the study by Milne et al. (2010)[21]. Six other studies [23-28] were excluded due to complete overlap with the aforementioned studies by Milne et al. [21,22]. In Azerbaijan, the study by Gholami et al. (2011) [29] was also excluded due to overlap with a more recent publication of the same author [30]. Five eligible studies from Brazil [31-35] were excluded due to overlap with the study by Ferreira et al. (2013) [36]. Regarding Canada, two studies [37,38] were excluded due to overlap with the study by MacArthur et al. (2008)[39]. From the studies conducted in the Province of Quebec, 12 studies [40-51] were excluded due to overlap with the Canadian arm of the multicenter study by Bailey et al. (2014) [52]. The Chinese study by Shi et al.[53] was also excluded due to overlap with another study also conducted in Shanghai by Gao et al. [54]. The Danish study by Kamper-Jørgensen et al. (2008) [55] was retained in the analysis; due to partial overlap (25-50%) with the study by Westergaard et al. (1997) [56], the respective study was removed in the sensitivity analysis.

Regarding France, the study by Rudant et al. (2008) [57] was excluded due to overlap with two more recent studies by Rudant et al. [58,59]; we retained only the ALL arm from the study by Rudant et al. (2012) [58] and the AML arm and Rudant et al. (2010) [59], as there was one more ALL case in the first one, while the latter encompassed one more AML case than the first one. Two German eligible studies [60,61] were excluded due to overlap with the study by Schuz et al. (1999) [62]. From the study by Schlehofer et al. (1996) [63] only the paternal arm was retained, as the maternal arm overlapped with the aforementioned study by Schuz et al.[62]. Regarding the multinational study by Roman et al. [64], both the German and the UK arms were retained as a whole, whereas the US arm was excluded due to overlap with the study by Mertens et al. (1998) [65].

Four Greek studies [66-69] were excluded due to overlap with the updated data provided by Professor E. Petridou from the NARECHEM database. Regarding the Greek-Swedish Study by Petridou et al. (2012) [70], only the Swedish arm was retained, as the Greek one was overlapping with the NARECHEM data. From the Italian study by Maule et al. (2007) [71] only the incremental analysis for maternal age data was kept, as the categorical analysis was excluded due to overlap with another study by the same author [72]. The paternal data in the aforementioned study were retained as a whole as they did not overlap with any other eligible study.

Regarding Sweden, two studies [73,74] were excluded due to overlap of their AML/maternal and ALL/maternal arms with the study by Larfors et al. (2012) [75] while their total leukemia/maternal arms were overlapping with the included study by Hemminki et al. (1999) [76]. Three more studies [77,78] were excluded due to overlap with the aforementioned study by Larfors et al. [75], whereas two other studies[79,80] were excluded due to overlap with the study by Hemminki et al. (1999) [76].

Concerning the studies conducted in the United Kingdom, the study by McKinney et al. (1999) [81] was excluded due to overlap of its ALL arm with the UK arm by the Roman et al. study [64], whereas its total leukemia arm was overlapping with another study by Roman et al. [82], out of which all the arms were kept except for the ALL one, as it overlapped with the larger study by Roman et al. [64].

Concerning studies conducted in the US, co-authors of several studies were contacted, in pursuit of clarifying issues pertaining to overlap. Specifically. co-authors of two studies, conducted in New York [83,84] kindly provided more data regarding their mutual overlap, which was considered to be up to 54%; therefore, both of them were excluded due to >50% overlap with the study by Mertens et al. [65]. Moreover, co-authors of the Californian study by Oksuzyan et al.[85] and the multicenter study by Johnson et al.[86] were asked about the potential overlap of their Californian study population. As the overlap with Johnson et al.[86] as well as Mertens et al.[65] was found to be partial (25-50%), the study by Oksuzyan et al.[85] was retained and subsequently removed in the sensitivity analysis. Finally, co-authors of five Children’s Oncology Group (COG) studies [65,87-90] were asked to provide a list of all the COG centers participating in the respective studies.

Subsequently, five US studies [88,91-94] were excluded due to overlap with the multicenter study by Mertens et al.[65]. Another study [89] was excluded due to overlap with Johnson et al. (2010).[90]. Two studies conducted in Texas [95,96] were excluded due to overlap with the multicenter study by Johnson et al. (2009)[86]. 16 Californian studies [97-112] were also excluded due to overlap with that by Oksuzyan et al. (2012)[85]. Moreover the multicenter study by Wen et al. (2000)[113] was excluded due to overlap with Mertens et al.[65] and another publication by Wen et al.(1998)[87]. Three more multicenter studies[114-116] were excluded due to overlap with Wen et al. (1998) [87], while two other multicenter studies[117,118] overlapped with the article by Mertens et al.[65]. Finally, the multicenter study by Linabery et al.[119] was not included due to overlap with that by Johnson et al. (2010).[90]

Regarding the study by Johnson et al. [120], we retained it in the analysis but due to partial overlap (25-50%) with the studies by Mertens et al.[65] and Johnson et al. (2009)[86] we removed it in the sensitivity analysis. From the study by Podvin et al.(2006), conducted in Washington [121], we excluded the total leukemia/maternal and total leukemia/paternal arms due to overlap with Johnson et al. [86]; the arms of AML and ALL were retained and removed in the sensitivity analysis due to partial overlap (25-50%) with the study by Mertens et al.[65] and Johnson et al. (2009) [86]. From another Texan study by Sprehe et al. (2010) [122], the arms of total leukemia were removed in the sensitivity analysis due to partial overlap (25-50%) with Johnson et al. (2009) [86]. Finally, from the multicenter study by Johnson et al. (2009) [86] both the AML and the ALL arms were excluded due to overlap with multiple studies [65,85,120-122].

Regarding the multicenter study of the Childhood Leukemia International Consortium (CLIC) by Bailey et al. [52], the whole Canadian, German, Greek (1993-1994) and New Zealand arms were retained, whereas only the paternal data of France (ADELE, ESCALE study), Italy and UK arms were kept as the maternal data overlapped with the included studies by Jourdan-Da Silva et al. [123], Rudant et al. [58,59], Farioli et al.[124] and Roman et al. [64,82], respectively. The Greek arm for the period 1996-2010 was excluded due to overlap with the updated NARECHEM data, whereas the US arms were also excluded due to overlap with the studies by Mertens et al.[65] and Oksuzyan et al.[85].

Taken as a whole, 69 articles (corresponding to 77 studies) were included in this meta-analysis; 39 articles reported only on maternal age [21,36,58,59,62,64,70,72,82,90,120,121,123,125-150], three reported only on paternal age [22,63,151] and 27 articles provided data both for maternal and paternal age [18,30,39,52,54-56,65,71,75,76,85-87,122,124,152-161].

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