Oral Oncology 50 (2014) 269–275

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Oral Oncology

journal homepage: www.elsevier .com/locate /ora loncology

Alcohol drinking and upper aerodigestive tract cancer mortality:A systematic review and meta-analysis

1368-8375/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.oraloncology.2013.12.015

⇑ Corresponding author. Address: Department of Epidemiology and Biostatistics,Zhejiang University School of Public Health, 866 Yuhangtang Road, Hangzhou310058, China. Tel.: +86 0571 88208193; fax: +86 0571 88208194.

E-mail address: jinmj@zju.edu.cn (M. Jin).1 These authors contributed equally to this work.

YingJun Li a,1, YingYing Mao a,1, Yang Zhang a, ShaoFang Cai a, GuangDi Chen b, Ye Ding a, Jing Guo a,Kun Chen a, MingJuan Jin a,⇑a Department of Epidemiology and Biostatistics, Zhejiang University School of Public Health, Hangzhou, Chinab Institute of Environmental Health, Zhejiang University School of Medicine, Hangzhou, China

a r t i c l e i n f o

Article history:Received 21 September 2013Received in revised form 29 November 2013Accepted 15 December 2013Available online 7 January 2014

Keywords:AlcoholUpper aerodigestive tract cancerMortalityMeta-analysisSystematic reviewEpidemiological study

s u m m a r y

Objectives: Upper aerodigestive tract (UADT) cancer is among the most frequent cancer and the mostcommon death causes of cancer in the world. Epidemiological studies have reported an inconsistent rela-tionship between alcohol drinking and UADT cancer mortality. However, no systematic review or meta-analysis has been reported up to now. To quantify the association between alcohol drinking and UADTcancer mortality, we performed this meta-analysis.Methods: A literature search was carried out in PubMed and ISI Web of Science to identify all relevantepidemiological studies published before June 30, 2013. And the categorical and dose–response meta-analyses were used to evaluate the association between alcohol drinking and UADT cancer mortality.Results: Ten studies involving 2976 UADT cancer deaths were included. Compared with non/occasionaldrinkers, the pooled relative risks (RRs) of UADT cancer mortality were 2.01 [95% confidence interval(CI) = 1.56–2.59] for any, 1.26 (95% CI = 0.94–1.67) for light (612.5 g/day), 1.79 (95% CI = 1.26–2.53) formoderate (12.6–49.9 g/day), and 3.63 (95% CI = 2.63–5.00) for heavy (P50 g/day) drinkers, respectively.Dose–response analysis showed that the increment in daily alcohol consumption was associated with anincreased risk of UADT cancer mortality continuously.Conclusion: This study provides evidence of a positive association between alcohol drinking and UADTcancer mortality, especially when alcohol consumption reaching moderate-to-heavy level. Thus, publichealth recommendation on UADT cancer prevention and control should consider limiting the intake ofalcoholic beverages.

� 2013 Elsevier Ltd. All rights reserved.

Introduction

Upper aerodigestive tract (UADT) cancer, including the cancerof oral cavity, pharynx, larynx, and esophagus, is among the mostfrequent cancer and the most common death causes of cancer inthe world [1]. Although the multifactorial origins of these cancershave been well-investigated, their etiology remains unclear tosome extent. Previous studies have reported that tobacco smokingand alcohol drinking are the major lifestyle-related risk factors,and the combined exposure leads to a multiplicative risk for thesecancers [2–8].

Alcohol drinking has been proven to be positively associatedwith UADT cancer incidence by several meta-analyses and sys-

tematic reviews [9–15]. However, there is still substantial uncer-tainty whether any potential relation between alcohol drinkingand UADT cancer mortality is true or just due to residual con-founding by smoking or other factors. First, the results from dif-ferent epidemiological studies on the association betweenalcohol drinking and UADT cancer mortality are discordant.Some studies show that moderate-to-heavy but not light drink-ing increases the risk of UADT cancer mortality [16], whileothers show that even low level of alcohol drinking is also asso-ciated with an elevated risk of UADT cancer mortality [17–19].Second, previous meta-analyses have shown a J-shaped relation-ship between alcohol drinking and all-cause [20,21] andall-cancer mortality [22]. Nevertheless, no systematic review ormeta-analysis has been reported the relationship between alco-hol drinking and UADT cancer mortality.

To quantify the association between alcohol drinking and UADTcancer mortality, we conducted a meta-analysis of epidemiologicalstudies published up to June 30, 2013.

270 Y. Li et al. / Oral Oncology 50 (2014) 269–275

Materials and methods

Literature search and study inclusion

A systematic literature search was performed in PubMed and ISIWeb of Science to identify all potentially relevant epidemiologicalstudies up to June 30, 2013. The search strategy was as follows:(alcohol OR alcoholic beverages) AND cancer AND mortality AND(prospective OR cohort OR case-control OR case-cohort). All titlesand abstracts were reviewed by two of the authors (Li and Mao). Ifeither of them included the study, the full-text paper was obtainedfor further reviewing. The reference lists of all full-text papers andreviews identified through the above search were manually checkedto identify additional publications of interest.

The studies which met the following explicit criteria were in-cluded: (i) case-control, case-cohort or cohort study design wereused; (ii) the exposure of interest was alcohol drinking; (iii) theendpoint of interest was the death from UADT (oral cavity, phar-ynx, larynx and esophagus) cancer; (iv) risk estimates [odds ratio(OR), risk ratio (RR), or hazard ratio (HR)] and corresponding 95%confidence intervals (CIs) or sufficient data to calculate them werereported; and (v) never and/or occasional (non/occasional) drink-ing was taken as the reference category. When several reportswere from the same study, only the most informative one wasincluded.

Data extraction and quality assessment

For each eligible study, the following information was ex-tracted, including publication year, country, study name, cancer

Figure 1. Flowchart o

site, number of subjects, study period, study design, gender, age,variables adjusted or matched, categories of alcohol drinking, riskestimates and corresponding 95% CIs.

Two reviewers (Li and Mao) independently assessed the qualityof included studies by scoring according to a set of structured cri-teria which has been published in previous study (see Appendix A)[22]. The score ranges from 0 (the lowest) to 10 (the highest), and ahigher score means better quality. The predetermined criteria wasdeveloped around the following three aspects: the representationof objects, the method of alcohol consumption data collection,and the method of data analysis. The discrepancies were resolvedby consensus and discussion.

Statistical analysis

The multivariate-adjusted risk estimates were selected if theywere reported in the original publication, otherwise the unad-justed risk estimates were calculated using the original data.

Since different units were used to measure alcohol intake in dif-ferent studies, it was converted into grams (g) of ethanol per day asa uniform measurement. The conversion was conducted accordingto the definition in the original article, and then the followingtransformation formulas were used if it was unavailable: 28 g ofethanol for 1 oz of alcohol, 12.5 g for 1 drink, and 0.8 g for 1 ml.The central value was treated as the corresponding exposure dosewhen a range of alcohol consumption was provided. While foropen-ended exposure category, the exposure dose was defined asthe lower bound added to the three-quarters of the adjacent previ-ous category [23]. The study-specific risk estimates were obtained

f study selection.

Y. Li et al. / Oral Oncology 50 (2014) 269–275 271

for light, moderate, and heavy drinking, which were equal to etha-nol intake of 612.5 g/day (61 drink/day), 12.6–49.9 g/day (2–3drinks/day), and P50 g/day (P4 drinks/day), respectively [24]. Ifmore than one exposure category fell into one of these three levelsin the original study, the corresponding estimates were synthe-sized using the method proposed by Hamling et al. [25]. Whilethe study reported the risk estimates not using non/occasionaldrinking as reference category, they were recalculated by theOrsini method if the non/occasional drinking data is available [26].

The heterogeneity among studies was assessed using Cochran Qtest [27] and I-squared statistic [28], defining a significant hetero-geneity as P 6 0.10 and/or I2 P 50%. The fixed-effects model wasapplied when no significant heterogeneity was presented; other-wise the random-effects model was used to provide more conser-vative estimates [29]. The forest plots for the association betweenalcohol drinking and UADT cancer mortality were generated forany, light, moderate, and heavy drinking versus non/occasionaldrinking. Meanwhile, subgroup analyses were carried out stratifiedby cancer site, gender, source of subjects, geographic area, majorconfounders (age, gender, and cigarette smoking) adjusted ormatched, length of follow-up, and quality score. In the subgroupanalysis on cancer site, only esophagus cancer was analyzed sepa-rately as the data from other types of UADT cancer is limited. Weassumed the nonlinearity in the dose–risk relation between alco-hol consumption and UADT cancer mortality, and the dose–re-sponse analyses were carried out using the flexible restrictedcubic splines method [30].

Publication bias was assessed by Egger’s linear regression [31]and Begg’s rank correlation [32]. The Begg’s funnel plots were alsodrawn, of which asymmetry was equated with the existence of po-tential publication bias. All statistical analyses were carried out inSTATA version 11.0 (STATA Corp, College Station, Texas) and SAS

Table 1Characteristics of studies on alcohol intake and UADT cancer mortality included in the me

Study Country and name of the study Cancer site Qualityscore

No. ofdeath/cases

Size ocohorNo. ofcontro

Potternet al.[38]

USA, Black males inWashington

Esophagus 5 90 213

Konoet al.[33]

Japan, Male physicians inwestern Japan

UADT 7 18 4643

Boffettaet al.[16]

USA, American Cancer SocietyProspective Study

Esophagusand oralcavity

7 185and155

29078(PY)

Panet al.[37]

China, Chicago Peoples GasCompany Study

Esophagus 7.5 125 250

Ide et al.[34]

Japan, Japan CollaborativeCohort Study for Evaluation ofCancer

Oral cavityandpharynx

6 52 11079(PR)

Ozasaet al.[35]

Japan, Japan CollaborativeCohort Study for Evaluation ofCancer

Esophagus 5.5 180 12913(PY)

Kimet al.[18]

Korea, Korea National HealthInsurance Corporation’s HealthExaminee Cohort in 2000

Esophagus,pharynx,and larynx

6 213,46,and49

13413(PY)

Yi et al.[17]

Korean, Kangwha cohort Esophagus 8.5 19 2696

Kimmet al.[36]

Korean, Korean CancerPrevention Study

Esophagus 4.5 996 92816(PY)

Yanget al.[19]

China, China’s national DiseaseSurveillance Points

Esophagus 8.5 848 21818(PR)

RP, person at risk; PY, person-year; M, male; F, female; BMI, body-mass index.

version 9.2 (SAS Institute Inc., Cary, NC). P < 0.05 was consideredstatistically significant.

Results

Literature search and study characteristics

Fig. 1 provides the flowchart of the literature search and studyinclusion. 2895 Articles were identified in the initial search, and2864 studies were excluded after screening their titles and ab-stracts because of obvious irrelevance. 21 Studies were next ex-cluded after full-text paper review, as 11 of them did not focuson mortality, 8 provided insufficient data, 1 was an updated studyfrom the same cohort, and 1 used ever drinking as the referencecategory. Finally, 10 studies published between 1981 and 2012were included for further analyses, including 8 prospective cohort[16–19,33–36], 1 nested case-control [37], and 1 case-control stud-ies [38].

The detailed characteristics of the 10 studies [16–19,33–38] aregiven in Table 1. Eight studies were conducted in Asia and two inNorth America. Eight studies reported on esophagus cancer, twoon oral cavity cancer, two on pharyngeal cancer, one on laryngealcancer, and one on all UADT cancer. The range of study periodsacross studies was from 1959 to 2006. A total of 2976 UADT cancerdeaths were included.

Alcohol drinking and UADT cancer mortality

Fig. 2 gives the forest plots that provide study-specific andpooled RRs (95% CIs) of UADT cancer mortality for any, light, mod-erate, and heavy drinking in strata of cancer site. The pooled RRs of

ta-analysis.

ft/

ls

Studyperiod

Design Gender;age

Variables adjusted or matched

1975–1977

Case-control

M; 59 Age

(PR) 1965–1983

Cohort M; 27–89

Age and smoking

72 1959–1971

Cohort M; 40–59

Age and smoking

1980–1988

Nestedcase-control

M; / Age

2 1988–1990

Cohort M, F;40–79

Age, smoking status, consumption ofgreen tea, preference for salty foods, andconsumption of green yellow vegetables

61 1988–1990

Cohort M, F; / Age and area

93 2001–2005

Cohort M; 40–69

Age, residential, smoking status, regularexercise, BMI, systolic and diastolic bloodpressure, and fasting blood sugar

(PR) 1985–2005

Cohort M; P55 Age, history of chronic disease, smokinghabit, ginseng intake, pesticide use, BMI,and education status

77 1993–2006

Cohort M; 30–95

Age, BMI, aspartate aminotransferase, andexercise

9 1990–2004

Cohort M; 40–79

Age, area, smoking, and education

272 Y. Li et al. / Oral Oncology 50 (2014) 269–275

UADT cancer mortality for any, light, moderate, and heavy drinkingversus non/occasional drinking were 2.01 (95% CI = 1.56–2.59),1.26 (95% CI = 0.94–1.67), 1.79 (95% CI = 1.26–2.53) and 3.63(95% CI = 2.63–5.00), respectively. And the corresponding pooledestimates of esophagus cancer mortality were 1.86 (95%CI = 1.40–2.47), 1.43 (95% CI = 1.09–1.87), 1.92 (95% CI = 1.25–2.96), and 3.37 (95% CI = 2.30–4.93), respectively.

Subgroup meta-analysis

Table 2 presents the association between alcohol drinking andUADT cancer mortality among different subgroups stratified by po-tential modifying factors. For any drinking versus non/occasionaldrinking, no significant difference was found across strata of cancersite, gender, geographic area, major confounders adjusted ormatched, or length of follow-up. However, when stratified by qual-ity score, the association between alcohol drinking and UADT can-cer mortality was stronger in studies with P median quality score(RR = 2.20, 95% CI = 1.35–3.58) than those with < median qualityscore (RR = 1.98, 95% CI = 1.50–2.61; Pfor heterogeneity = 0.004).Meanwhile, the association was stronger in occupation-specificstudies (RR = 2.81, 95% CI = 1.43–5.52) than population-basedstudies (RR = 1.84, 95% CI = 1.40–2.41; Pfor heterogeneity = 0.001).While considering the concrete levels of alcohol drinking, the

Figure 2. Forest plots for pooled relative risks (RRs) and the corresponding 95% confidencheavy drinking in strata of cancer site.

meaningful stratified factors mainly included cancer site and geo-graphic area.

Dose–response meta-analysis

Fig. 3 describes the best-fitting dose–risk relationship of alcoholconsumption with UADT and esophagus cancer mortality. Thedose–response analysis indicated the increment in daily alcoholconsumption was associated with an increased risk of UADT cancermortality continuously, and a similar trend was observed in esoph-agus cancer. The estimated RRs for UADT and esophagus cancermortality reached 4.73 (95% CI = 3.93–5.69) and 2.91 (95%CI = 2.45–3.46) for a daily intake of 86.5 and 87.5 g as the top ofcurves, respectively. The male-specific dose–response analysisshowed similar result (data not shown).

Sensitivity and publication bias analyses

The sensitivity analysis showed that the pooled results did notchange evidently even if the most influential study was omitted(data not shown). All Begg’s funnel plots appeared to be symmet-rical (see Appendix A), and no significant asymmetry was foundby the Egger’s and Begg’s tests (P > 0.05).

e intervals (CIs) of UADT cancer mortality for (A) any, (B) light, (C) moderate, and (D)

Y. Li et al. / Oral Oncology 50 (2014) 269–275 273

Discussion

The results of the present meta-analysis provide evidence for apositive association between alcohol drinking and UADT cancermortality. On one hand, the categorical meta-analysis found that,compared with non/occasional drinking, alcohol drinking wasassociated with an significantly increased risk at moderate (12.6–49.9 g/day) and heavy level (P50 g/day), and a marginal increasedrisk at light level (612.5 g/day) for UADT cancer mortality; whilean significantly increased risk for esophagus cancer mortality atall three levels. On the other hand, the dose–response meta-analy-sis showed that the increment in daily alcohol consumption wasassociated with a continuously increased risk of UADT and esoph-agus cancer mortality. The minor discrepancy between categoricaland dose–response meta-analysis at light level for UADT cancermortality may likely be explained by the different methods ap-plied. Furthermore, the curves of dose–risk relation declined afterdaily alcohol consumption reaching 86.5 and 87.5 g for UADT andesophagus cancer mortality, respectively. This may be derivedfrom that the data is so limited at such a high level of alcohol con-sumption but not a real effect.

Light alcohol drinking was negatively associated with all cancer[22,39] and all-cause mortality in previous meta-analyses [20].However, it was associated with a marginally increased risk ofUADT cancer mortality and a significantly increased risk of esoph-agus cancer mortality in the present study. The discordance sug-gests the possibly differential effect of alcohol drinking ondifferent types of diseases and cancers. Additionally, though sev-eral meta-analyses and systematic reviews have supported a posi-tive association between alcohol drinking and UADT cancerincidence [9–15], our study is the first meta-analysis providingdefinite evidence for a positive association between alcohol

Table 2Pooled and subgroup analysis stratified by potential modifying factors.

Drinking vs. non/occasionala Light vs. non

Nb RR/OR (95%CI) P valuec Nb RR/OR (9

All studies 10 2.01(1.56–2.59) – 5 1.26(0.94

Cancer siteEsophagus cancer 8 1.86(1.40–2.47) 0.081 5 1.43(1.09Other UADT cancer 4 2.43(1.39–4.24) 2 0.88(0.42

GenderMale 10 2.09(1.60–2.73) 0.594 5 1.26(0.94Female 2 1.38(0.64–2.97) 0 –

Source of subjectsPopulation-based 7 1.84(1.40–2.41) 0.001 4 1.16(0.94Occupation-specific (or hospital-based) 3 2.81(1.43–5.52) 1 1.90(1.58

Geographic areaAsia 8 1.93(1.46–2.54) 0.207 4 1.41(1.09North America 2 2.51(1.22–5.16) 1 0.78(0.23

Major confounders adjusted or matchedd

Yes 8 1.90(1.47–2.46) 0.141 5 1.26(0.94No or partially 2 3.41(0.86–13.46) 0 –

Length of follow-up<12 years 5 1.93(1.41–2.64) 0.566 1 1.25(0.90P12 years 5 2.16(1.42–3.27) 4 1.21(0.80

Quality score<6.55 5 1.98(1.50–2.61) 0.004 2 1.55(1.17P6.55 5 2.20(1.35–3.58) 3 1.01(0.64

RR, relative risk; OR, odds ratio; CI, confidence interval.a Reference group included nondrinkers and occasional drinkers; light was defined as6

and heavy as P50 g/day (P4 drinks/day).b The number of studies included.c P for heterogeneity test between strata.d Age, gender, and cigarette smoking.

drinking and UADT cancer mortality. Moreover, the InternationalAgency for Research on Cancer (IARC) working group has identifiedUADT cancer as alcohol-related cancer [40].

This study indicates that the association between alcohol drink-ing and UADT cancer mortality differed by cancer site. A signifi-cantly increased risk of esophagus cancer mortality was found atall three levels of alcohol drinking; whereas similar associationwas only found for other UADT cancer (oral cavity, pharynx, andlarynx) at high level. For one thing, the effect of alcohol on UADTcancer varies by specific cancer site. Previous studies have shownthat alcohol increases gastroesophageal reflux by relaxing the low-er esophageal sphincter, and a positive relationship between alco-hol drinking and esophagus cancer is biologically plausible [41,42].For another thing, the inconsistance may occur because of the lim-ited amount of available studies on other UADT cancer mortality.Therefore, more epidemiological studies are needed to ascertainthe association between alcohol drinking and oral cavity, pharyn-geal and laryngeal cancer mortality.

We found significant differences between subgroups stratifiedby source of subjects and quality score in any drinking versusnon/occasional drinking. A stronger association between alcoholdrinking and UADT cancer mortality was found in studies with -P median quality score than those with < median quality score.The association between alcohol drinking and UADT cancer mortal-ity was also stronger among people from North America than thosefrom Asia at moderate and heavy level. One possible explanation isthat the proportion of moderate-to-heavy drinking is very low inAsian population. In fact, individuals with the higher prevalanceof the polymorphisms of ethanol metabolism related genes [e.g.alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH)]tend to be discouraged from drinking excessive alcohol, and havea lower risk of death from alcohol-related cancer consequently

/occasionala Moderate vs. non/occasionala Heavy vs. non/occasionala

5%CI) P valuec Nb RR/OR (95%CI) P valuec Nb RR/OR (95%CI) P valuec

–1.67) – 9 1.79(1.26–2.53) – 10 3.63(2.63–5.00) –

–1.87) 0.028 7 1.92(1.25–2.96) 0.662 8 3.37(2.30–4.93) 0.044–1.84) 4 1.51(0.77–2.96) 4 4.19(2.32–7.55)

–1.67) – 9 1.77(1.22–2.55) 0.859 10 3.63(2.63–5.00) –1 2.06(0.74–5.73) 0 –

–1.43) 0.0 6 1.68(1.11–2.55) 0.001 7 3.69(2.54–5.35) 0.477–2.28) 3 2.51(1.82–3.46) 3 3.67(1.62–8.33)

–1.83) 0.053 8 1.48(1.06–2.06) 0.0 8 2.97(2.15–4.09) 0.0–2.59) 1 4.27(2.62–6.96) 2 6.11(4.34–8.60)

–1.67) – 8 1.83(1.27–2.64) 0.430 8 3.73(2.66–5.25) 0.1791 1.27(0.47–3.40) 2 3.41(0.86–13.46)

–1.73) 0.229 4 1.29(0.97–1.73) 0.003 5 3.03(2.20–4.18) 0.341–1.84) 5 2.61(1.48–4.61) 5 4.47(2.50–7.98)

–2.05) 0.003 4 1.50(1.00–2.26) 0.396 5 3.44(2.70–4.39) 0.612–1.59) 5 2.34(1.15–4.76) 5 4.06(2.12–7.79)

12.5 g/day of ethanol (61 drink/day), moderate as 12.6–49.9 g/day (2–3 drinks/day),

Figure 3. Relative risks (RRs) (solid line) and the corresponding 95% confidence intervals (CIs) (dash lines) for the dose–risk relationship between alcohol consumption(grams per day) with (A) UADT and (B) esophagus cancer mortality. The P values for the nonlinearity test were all <0.001. Data fitting was based on fixed-effects restrictedcubic splines models using the fixed percentiles 5%, 35%, 65%, and 95% as knot locations.

274 Y. Li et al. / Oral Oncology 50 (2014) 269–275

[43,44]. Another possible reason is that the number of studies fromNorth America is very limited. Moreover, no epidemiological studyon the association between alcohol drinking and UADT cancermortality has been published from South American, African orEuropean populations.

The strengths and potential limitations of this meta-analysisdeserve mention. In the present study, the association betweenalcohol drinking and UADT cancer mortality has been evaluatedcomprehensively and stratified by many potential modifying fac-tors. Furthermore, robust results were obtained from sensitivityanalysis, and there was no significant publication bias. Besides,the combinative use of traditional categorical meta-analysisand dose–response analysis would provide more meaningfulinformation [45]. Nevertheless, statistically significant heteroge-neity among studies was observed, which was likely to be attrib-uted to the variation in study design and quality. However, theuse of random-effects model was allowed to take into accountthe heterogeneity among studies [29]. Additionally, the type ofalcoholic beverage, the lifetime exposure to alcohol, and thedrinking pattern were not studied in this meta-analysis as onlya small proportion of the original studies provided these infor-mation. Finally, only two studies [16,34] provided female-specificdata at different levels of alcohol drinking, which precluded usfrom conducting the in-depth dose–response meta-analysis infemale.

In conclusion, the present meta-analysis provides evidence of apositive association between alcohol drinking and UADT cancermortality, especially at moderate-to-heavy level. Thus, publichealth recommendations on UADT cancer prevention and controlshould consider limiting the intake of alcoholic beverages. How-ever, further large-sample, well-designed, prospective epidemio-logical studies, especially for women, are needed to confirm ourfindings.

Conflict of interest statement

None declared.

Acknowledgements

We thank Ruifeng Li and Donna Spiegelman from the Depart-ment of Epidemiology, Harvard School of Public Heath, for gener-

ously providing the SAS %METADOSE macro. This work wassupported by National Natural Science Foundation of China (GrantNos. 30800942, 81072356).

Appendix A. Supplementary material

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.oraloncolo-gy.2013.1 2.015.

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