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Processed Meat Consumption and Stomach Cancer Risk A Meta-Analysis.txt
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Processed Meat Consumption and Stomach Cancer Risk A Meta-Analysis.txt
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<div class="article fulltext-view" itemprop="articleBody"><span class="highwire-journal-article-marker-start"></span><h1 id="article-title-1" itemprop="headline">Processed Meat Consumption and Stomach Cancer Risk: A Meta-Analysis</h1>
<div class="contributors">
<ol class="contributor-list" id="contrib-group-1">
<li class="contributor" id="contrib-1" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Susanna+C.+Larsson&sortspec=date&submit=Submit">Susanna C. Larsson</a></span>,
</li>
<li class="contributor" id="contrib-2" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Nicola+Orsini&sortspec=date&submit=Submit">Nicola Orsini</a></span> and
</li>
<li class="last" id="contrib-3"><span class="name"><a class="name-search"
href="/search?author1=Alicja+Wolk&sortspec=date&submit=Submit">Alicja Wolk</a></span></li>
</ol>
<ol class="affiliation-list">
<li class="aff"><a id="aff-1" name="aff-1"></a><address><em>Affiliation of authors:</em> Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm,
Sweden
</address>
</li>
</ol>
<ol class="corresp-list">
<li class="fn" id="corresp-1"><em>Correspondence to:</em> Susanna C. Larsson, MSc, Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska
Institutet, Box 210, SE-171 77, Stockholm, Sweden (e-mail: <span class="em-link"><span class="em-addr">susanna.larsson{at}ki.se</span></span>).
</li>
</ol>
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<li xmlns:hwp="http://schema.highwire.org/Journal" class="received"
hwp:start="2005-12-23"><span class="received-label">Received </span>December 23, 2005.
</li>
<li xmlns:hwp="http://schema.highwire.org/Journal" class="rev-recd"
hwp:start="2006-05-11"><span class="rev-recd-label">Revision received </span>May 11, 2006.
</li>
<li xmlns:hwp="http://schema.highwire.org/Journal" class="accepted"
hwp:start="2006-06-14"><span class="accepted-label">Accepted </span>June 14, 2006.
</li>
</ul>
</div>
<div class="section abstract" id="abstract-1" itemprop="description">
<div class="section-nav">
<div class="nav-placeholder"> </div><a href="#sec-1" title="SUBJECTS AND METHODS" class="next-section-link"><span>Next Section</span></a></div>
<h2>Abstract</h2>
<p id="p-1"><em>Background:</em> The relationship between processed meat consumption and the risk of stomach cancer is controversial. We conducted a meta-analysis
to summarize available evidence from cohort and case–control studies on this issue. <em>Methods:</em> We searched Medline for studies of processed meat consumption and stomach cancer published from January 1966 through March
2006. Random-effects models were used to pool the relative risks from individual studies. All statistical tests were two-sided.
<em>Results:</em> Six prospective cohort studies (involving 2209 stomach cancer patients) and nine case–control studies (2495 case patients)
were eligible for inclusion in the dose–response meta-analysis of processed meat consumption. The estimated summary relative
risks of stomach cancer for an increase in processed meat consumption of 30 g/day, approximately half of an average serving,
were 1.15 (95% confidence interval [CI] = 1.04 to 1.27) for the cohort studies and 1.38 (95% CI = 1.19 to 1.60) for the case–control
studies. There was no statistically significant heterogeneity among the cohort studies (<em>P</em> = .42) or among the case–control studies (<em>P</em> = .19). In three cohort and four case–control studies that examined the association between bacon consumption and stomach
cancer, the summary relative risk was 1.37 (95% CI = 1.17 to 1.61) for the highest versus lowest intake categories of bacon,
without heterogeneity among these studies (<em>P</em> = .66). <em>Conclusion:</em> Increased consumption of processed meat is associated with an increased risk of stomach cancer. However, the possibility
that the association may be confounded or modified by other factors cannot be ruled out.
</p>
</div>
<p id="p-2">Despite a steady global decline in stomach cancer incidence and mortality over the last 50 years, this malignancy remains
the second leading cause of cancer death worldwide <em>(<a id="xref-ref-1-1" class="xref-bibr" href="#ref-1">1</a>)</em>. In fact, stomach cancer accounts for nearly 10% of all cancer deaths and claims approximately 700 000 lives annually <em>(<a id="xref-ref-1-2" class="xref-bibr" href="#ref-1">1</a>)</em>. Because the prognosis is poor, identification of risk factors amenable for modification could have a marked impact on reducing
stomach cancer morbidity and mortality. Infection with <em>Helicobacter pylori</em> is strongly implicated in stomach cancer etiology <em>(<a id="xref-ref-2-1" class="xref-bibr" href="#ref-2">2</a>,<a id="xref-ref-3-1" class="xref-bibr" href="#ref-3">3</a>)</em>. Nevertheless, only a small proportion of people infected with the bacterium develop stomach cancer, suggesting that such
infection is not sufficient itself to cause this malignancy.
</p>
<p id="p-3">The decline in incidence rates of stomach cancer has been proposed to be attributable, at least in part, to improvements in
diet and food storage and, in particular, the introduction of refrigeration. In addition to increased year-round availability
of fresh fruits and vegetables, refrigeration has reduced the need for salt and other methods of food preservation. Processed
meat includes foods preserved by salting, smoking, or adding nitrates or nitrites. Diets high in salt could damage the gastric
mucosa, leading to gastritis, increased DNA synthesis, and excessive cell replication <em>(<a id="xref-ref-4-1" class="xref-bibr" href="#ref-4">4</a>–<a id="xref-ref-6-1" class="xref-bibr" href="#ref-6">6</a>)</em>. Processed meat often contains, besides high amounts of salt, carcinogenic <em>N</em>-nitroso compounds <em>(<a id="xref-ref-7-1" class="xref-bibr" href="#ref-7">7</a>–<a id="xref-ref-9-1" class="xref-bibr" href="#ref-9">9</a>)</em>. Although an association between processed meat consumption and stomach cancer risk is biologically plausible, epidemiologic
studies on this relationship have yielded inconsistent results.
</p>
<p id="p-4">A systematic and quantitative assessment of published findings on the association between processed meat consumption and risk
of stomach cancer is not available. Therefore, we used meta-analysis as a systematic approach to summarize evidence from cohort
and case–control studies on this issue.
</p>
<div class="section" id="sec-1">
<div class="section-nav"><a href="#abstract-1" title="Abstract" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-6" title="RESULTS" class="next-section-link"><span>Next Section</span></a></div>
<h2>S<span class="sc">UBJECTS AND</span> M<span class="sc">ETHODS</span></h2>
<h3>Search Strategy</h3>
<p id="p-5">To identify epidemiologic studies of processed meat consumption and risk of stomach cancer, we conducted a literature search
in Medline for articles published in any language from January 1966 through March 2006. We used the following medical subject
heading terms and/or text words: “meat” or “foods” combined with “stomach cancer,” “stomach neoplasm,” “gastric cancer,” or
“gastric neoplasm.” We also searched the reference lists of pertinent publications manually to identify additional studies.
</p>
<h3>Study Selection</h3>
<p id="p-6">To be included in our meta-analysis, studies had to 1) be a cohort or case–control study with stomach cancer incidence or
mortality as the outcome and 2) provide relative risk estimates with confidence intervals (or information to compute them)
of stomach cancer associated with processed meat consumption. Processed meat was taken to include any of the following meat
items: bacon, sausage, hot dogs, salami, and ham. We considered “cured meat,” “preserved meat,” “salted meat,” and “smoked
meat” as equivalent to “processed meat.”
</p>
<p id="p-7">We identified 11 prospective cohort studies <em>(<a id="xref-ref-10-1" class="xref-bibr" href="#ref-10">10</a>–<a id="xref-ref-20-1" class="xref-bibr" href="#ref-20">20</a>)</em> and 22 case–control studies <em>(<a id="xref-ref-21-1" class="xref-bibr" href="#ref-21">21</a>–<a id="xref-ref-42-1" class="xref-bibr" href="#ref-42">42</a>)</em> with data that were potentially eligible for inclusion in the meta-analysis. One cohort study <em>(<a id="xref-ref-10-2" class="xref-bibr" href="#ref-10">10</a>)</em> and three case–control studies <em>(<a id="xref-ref-27-1" class="xref-bibr" href="#ref-27">27</a>,<a id="xref-ref-32-1" class="xref-bibr" href="#ref-32">32</a>,<a id="xref-ref-34-1" class="xref-bibr" href="#ref-34">34</a>)</em> were excluded for the following reasons: no relative risks <em>(<a id="xref-ref-10-3" class="xref-bibr" href="#ref-10">10</a>)</em> or confidence intervals <em>(<a id="xref-ref-27-2" class="xref-bibr" href="#ref-27">27</a>)</em> were provided and could not be calculated, the relative risk was for 1 standard deviation difference in processed meat consumption
<em>(<a id="xref-ref-32-2" class="xref-bibr" href="#ref-32">32</a>)</em>, or the exposure was nonspecific (mixed with eggs) <em>(<a id="xref-ref-34-2" class="xref-bibr" href="#ref-34">34</a>)</em>. The remaining 10 cohort studies <em>(<a id="xref-ref-11-1" class="xref-bibr" href="#ref-11">11</a>–<a id="xref-ref-20-2" class="xref-bibr" href="#ref-20">20</a>)</em> and 19 case–control studies <em>(<a id="xref-ref-21-2" class="xref-bibr" href="#ref-21">21</a>–<a id="xref-ref-26-1" class="xref-bibr" href="#ref-26">26</a>,<a id="xref-ref-28-1" class="xref-bibr" href="#ref-28">28</a>–<a id="xref-ref-31-1" class="xref-bibr" href="#ref-31">31</a>,<a id="xref-ref-33-1" class="xref-bibr" href="#ref-33">33</a>,<a id="xref-ref-35-1" class="xref-bibr" href="#ref-35">35</a>–<a id="xref-ref-42-2" class="xref-bibr" href="#ref-42">42</a>)</em> were included in the meta-analysis.
</p>
<h3>Data Extraction</h3>
<p id="p-8">We extracted from each publication the following data: the first author's last name, the year of publication, the country
in which the study was performed, study design, the sample size, the type of control subjects (in case–control studies), duration
of follow-up (in cohort studies), variables controlled for by matching or in the multivariable model, and the relative risks
with corresponding confidence intervals for each category of processed meat consumption and/or for processed meat consumption
as a continuous variable. From each study, we extracted the relative risk estimates that reflected the greatest degree of
control for potential confounders.
</p>
<h3>Statistical Analysis</h3>
<p id="p-9">Relative risk (RR) was used as the measure of the association of processed meat consumption with stomach cancer risk. Because
the absolute risk of stomach cancer is low, the odds ratios in case–control studies approximate the relative risks <em>(<a id="xref-ref-43-1" class="xref-bibr" href="#ref-43">43</a>)</em>; we therefore report all results as relative risks for simplicity. Relative risks from individual studies and corresponding
standard errors (derived from the confidence intervals) were transformed to their natural logarithms to stabilize the variance
and to normalize the distributions. We quantified the relationship between processed meat consumption and stomach cancer risk
with the method of DerSimonian and Laird <em>(<a id="xref-ref-44-1" class="xref-bibr" href="#ref-44">44</a>)</em> by using the assumptions of a random effects model, which incorporates both within- and between-study variability. When separate
relative risk estimates were provided for men and women <em>(<a id="xref-ref-15-1" class="xref-bibr" href="#ref-15">15</a>,<a id="xref-ref-18-1" class="xref-bibr" href="#ref-18">18</a>,<a id="xref-ref-40-1" class="xref-bibr" href="#ref-40">40</a>)</em>, we pooled the relative risks (weighted by the inverse of their variance) to obtain a single relative risk from each study.
For one case–control study <em>(<a id="xref-ref-29-1" class="xref-bibr" href="#ref-29">29</a>)</em> that used two control groups, the relative risks based on comparison with population control subjects were used in the overall
meta-analysis.
</p>
<p id="p-10">For the dose-response meta-analysis, we used the method proposed by Greenland and associates <em>(<a id="xref-ref-45-1" class="xref-bibr" href="#ref-45">45</a>,<a id="xref-ref-46-1" class="xref-bibr" href="#ref-46">46</a>)</em> to compute study-specific slopes (linear trends) from the correlated natural log of the relative risks across categories
of processed meat consumption. This method requires that the distribution of case patients and control subjects (or person–time)
and the relative risk with its variance estimate for at least three quantitative exposure categories be known. For studies
that did not provide the number of case patients and control subjects in each exposure category <em>(<a id="xref-ref-15-2" class="xref-bibr" href="#ref-15">15</a>,<a id="xref-ref-25-1" class="xref-bibr" href="#ref-25">25</a>,<a id="xref-ref-29-2" class="xref-bibr" href="#ref-29">29</a>,<a id="xref-ref-34-3" class="xref-bibr" href="#ref-34">34</a>,<a id="xref-ref-36-1" class="xref-bibr" href="#ref-36">36</a>,<a id="xref-ref-39-1" class="xref-bibr" href="#ref-39">39</a>–<a id="xref-ref-41-1" class="xref-bibr" href="#ref-41">41</a>)</em>, we estimated the slopes using variance-weighted least-squares regression models. We rescaled processed meat consumption
to grams per day using 50 g as the approximate average portion (serving) size <em>(<a id="xref-ref-47-1" class="xref-bibr" href="#ref-47">47</a>)</em>. For each study, the median or mean level of consumption for each category of processed meat was assigned to each corresponding
relative risk. When the median or mean consumption per category was not presented in the article, we assigned the midpoint
of the upper and lower boundaries in each category as the average consumption. If the upper boundary of the highest category
was not provided, we assumed that it had the same amplitude as the preceding category. When the lowest category was open-ended,
the lowest boundary was assumed to be zero. For three studies that reported relative risks for processed meat consumption
as a continuous variable <em>(<a id="xref-ref-19-1" class="xref-bibr" href="#ref-19">19</a>–<a id="xref-ref-21-3" class="xref-bibr" href="#ref-21">21</a>)</em>, we used these relative risks in the dose–response analysis. We used an increase in processed meat consumption of 30 g/day,
which is approximately half of an average serving. This cut point was chosen a priori; the same cut point had been used in
a previous meta-analysis of processed meat consumption and risk of colorectal cancer <em>(<a id="xref-ref-47-2" class="xref-bibr" href="#ref-47">47</a>)</em>. We checked for nonlinearity of the dose–response relationship between processed meat consumption and stomach cancer by estimating
polynomial models. However, the best-fitting model was a linear model.
</p>
<p id="p-11">Statistical heterogeneity among studies was evaluated using the <em>Q</em> and <em>I<sup>2</sup></em> statistics <em>(<a id="xref-ref-48-1" class="xref-bibr" href="#ref-48">48</a>)</em>. For the <em>Q</em> statistic, a <em>P</em><.1 was considered to be representative of statistically significant heterogeneity. <em>I</em><sup>2</sup> is the proportion of total variation contributed by between-study variation <em>(<a id="xref-ref-48-2" class="xref-bibr" href="#ref-48">48</a>)</em>. We conducted subgroup analyses by study design (cohort versus case–control), the type of control subjects (hospital-based
versus population-based) in case–control studies, the location of the study (North America, Europe, or Asia), and publication
year (before 2000 versus after). Separate analyses were performed for cohort and case–control studies when there was statistically
significant heterogeneity in the summary results between these study designs. Publication bias was assessed with Egger's regression
asymmetry test <em>(<a id="xref-ref-49-1" class="xref-bibr" href="#ref-49">49</a>)</em>; <em>P</em><.1 was considered to be representative of statistically significant publication bias. Statistical analyses were performed
with Stata, version 9.0 (StataCorp, College Station, TX). All statistical tests were two-sided.
</p>
</div>
<div class="section" id="sec-6">
<div class="section-nav"><a href="#sec-1" title="SUBJECTS AND METHODS" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-12" title="DISCUSSION" class="next-section-link"><span>Next Section</span></a></div>
<h2>R<span class="sc">ESULTS</span></h2>
<h3>Study Characteristics</h3>
<p id="p-12">Of the 10 prospective cohort studies, four were carried out in the United States (including one in Hawaii and one among men
of Japanese ancestry), four in Europe, and two in Japan (<a id="xref-table-wrap-1-1" class="xref-table" href="#T1">Table 1</a>). The study population consisted of men and women in seven cohort studies, of only men in two studies, and of only women
in one study. Sample sizes ranged from 3123 <em>(<a id="xref-ref-17-1" class="xref-bibr" href="#ref-17">17</a>)</em> to 970 045 <em>(<a id="xref-ref-15-3" class="xref-bibr" href="#ref-15">15</a>)</em>, and the number of stomach cancer cases varied from 68 <em>(<a id="xref-ref-14-1" class="xref-bibr" href="#ref-14">14</a>)</em> to 1349 <em>(<a id="xref-ref-15-4" class="xref-bibr" href="#ref-15">15</a>)</em>. In six studies, the outcome was stomach cancer incidence <em>(<a id="xref-ref-11-2" class="xref-bibr" href="#ref-11">11</a>,<a id="xref-ref-13-1" class="xref-bibr" href="#ref-13">13</a>,<a id="xref-ref-14-2" class="xref-bibr" href="#ref-14">14</a>,<a id="xref-ref-17-2" class="xref-bibr" href="#ref-17">17</a>,<a id="xref-ref-19-2" class="xref-bibr" href="#ref-19">19</a>,<a id="xref-ref-20-3" class="xref-bibr" href="#ref-20">20</a>),</em> and in four studies, the outcome was stomach cancer mortality <em>(<a id="xref-ref-12-1" class="xref-bibr" href="#ref-12">12</a>,<a id="xref-ref-15-5" class="xref-bibr" href="#ref-15">15</a>,<a id="xref-ref-16-1" class="xref-bibr" href="#ref-16">16</a>,<a id="xref-ref-18-2" class="xref-bibr" href="#ref-18">18</a>)</em>. The duration of follow-up was longer than 10 years in all but two studies <em>(<a id="xref-ref-17-3" class="xref-bibr" href="#ref-17">17</a>,<a id="xref-ref-19-3" class="xref-bibr" href="#ref-19">19</a>)</em>.
</p>
<div class="table pos-float" id="T1">
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<div class="table-caption"><span class="table-label"><strong>Table 1.</strong> </span>
<p id="p-13" class="first-child">Characteristics of prospective cohort studies of processed meat consumption and stomach cancer risk*</p>
<div class="sb-div caption-clear"></div>
</div>
</div>
<p id="p-17">Of the 19 case–control studies, three were conducted in the United States, seven in Europe, two in Japan, two in Uruguay,
and one each in Canada, Taiwan, China, Puerto Rico, and Mexico (<a id="xref-table-wrap-2-1" class="xref-table" href="#T2">Table 2</a>). The number of case patients enrolled in these studies ranged from 109 <em>(<a id="xref-ref-28-2" class="xref-bibr" href="#ref-28">28</a>)</em> to 741 <em>(<a id="xref-ref-26-2" class="xref-bibr" href="#ref-26">26</a>)</em>, and the number of control subjects varied from 123 <em>(<a id="xref-ref-28-3" class="xref-bibr" href="#ref-28">28</a>)</em> to 36 490 <em>(<a id="xref-ref-39-2" class="xref-bibr" href="#ref-39">39</a>)</em>. Control subjects were drawn from the general population (10 studies), hospitals (eight studies), or both (one study).
</p>
<div class="table pos-float" id="T2">
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<div class="table-caption"><span class="table-label"><strong>Table 2.</strong> </span>
<p id="p-18" class="first-child">Characteristics of case–control studies of processed meat consumption and stomach cancer risk*</p>
<div class="sb-div caption-clear"></div>
</div>
</div>
<h3>Processed Meat</h3>
<h4>Highest versus lowest intake category.</h4>
<p id="p-21">Seven cohort studies <em>(<a id="xref-ref-11-4" class="xref-bibr" href="#ref-11">11</a>,<a id="xref-ref-13-3" class="xref-bibr" href="#ref-13">13</a>–<a id="xref-ref-16-3" class="xref-bibr" href="#ref-16">16</a>,<a id="xref-ref-19-5" class="xref-bibr" href="#ref-19">19</a>,<a id="xref-ref-20-5" class="xref-bibr" href="#ref-20">20</a>)</em> and 14 case–control studies <em>(<a id="xref-ref-21-5" class="xref-bibr" href="#ref-21">21</a>,<a id="xref-ref-23-2" class="xref-bibr" href="#ref-23">23</a>–<a id="xref-ref-25-3" class="xref-bibr" href="#ref-25">25</a>,<a id="xref-ref-29-4" class="xref-bibr" href="#ref-29">29</a>,<a id="xref-ref-33-3" class="xref-bibr" href="#ref-33">33</a>,<a id="xref-ref-35-3" class="xref-bibr" href="#ref-35">35</a>–<a id="xref-ref-42-4" class="xref-bibr" href="#ref-42">42</a>)</em> examined the relationship between processed meat consumption and stomach cancer risk. For the meta-analysis comparing the
highest with the lowest consumption categories, two case–control studies were excluded because processed meat consumption
was analyzed as a continuous variable <em>(<a id="xref-ref-21-6" class="xref-bibr" href="#ref-21">21</a>)</em> or the study <em>(<a id="xref-ref-37-2" class="xref-bibr" href="#ref-37">37</a>)</em> was superseded by a later publication <em>(<a id="xref-ref-42-5" class="xref-bibr" href="#ref-42">42</a>)</em> based on the same population but with a larger sample size [the smaller study <em>(<a id="xref-ref-37-3" class="xref-bibr" href="#ref-37">37</a>)</em> was included in the dose–response meta-analysis because processed meat consumption was not quantified in the larger study
<em>(<a id="xref-ref-42-6" class="xref-bibr" href="#ref-42">42</a>)</em>].
</p>
<p id="p-22">There was statistically significant heterogeneity between the cohort and case–control studies in the summary relative risks
(<em>Q</em> = 2.85; <em>P</em> = .09). Combined, the seven cohort studies included 2277 stomach cancer patients. In these studies, the summary relative
risk of stomach cancer was 1.24 (95% confidence interval [CI] = 0.98 to 1.56; <a id="xref-fig-1-1" class="xref-fig" href="#F1">Fig. 1</a>) for individuals in the highest relative to the lowest category of processed meat consumption. The corresponding summary
relative risk for the 12 case–control studies (involving 3030 case patients) was 1.63 (95% CI = 1.31 to 2.01; <a id="xref-fig-2-1" class="xref-fig" href="#F2">Fig. 2</a>). Statistically significant heterogeneity was observed among the cohort studies (<em>Q</em> = 12.99; <em>P</em> = .04; <em>I</em><sup>2</sup> = 53.8%) and among the case–control studies (<em>Q</em> = 19.11; <em>P</em> = .06; <em>I</em><sup>2</sup> = 42.4%). Within each study design, the association between processed meat consumption and stomach cancer risk did not differ
statistically significantly by the location of the study or publication year (<em>P</em>>.1 for all). No publication bias was observed (<em>P</em> = .68 for cohort studies and <em>P</em> = .93 for case–control studies).
</p>
<div id="F1" class="fig pos-float odd">
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<div class="fig-caption"><span class="fig-label"><strong>Fig. 1.</strong></span>
<p id="p-23" class="first-child">Relative risks from cohort studies examining the association between processed meat consumption (highest versus lowest category)
and risk of stomach cancer. <strong>Squares</strong> indicate study-specific relative risks (<strong>size of the square</strong> reflects the study-specific statistical weight, i.e., the inverse of the variance); <strong>horizontal lines</strong> indicate 95% confidence intervals; <strong>diamond</strong> indicates summary relative risk estimate with its corresponding 95% confidence interval. Test for heterogeneity: <em>Q</em> = 12.99, <em>P</em> = .04, <em>I</em><sup>2</sup> = 53.8%. All statistical tests were two-sided.
</p>
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<div id="F2" class="fig pos-float odd">
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<div class="fig-caption"><span class="fig-label"><strong>Fig. 2.</strong></span>
<p id="p-24" class="first-child">Relative risks from case–control studies examining the association between processed meat consumption (highest versus lowest
category) and risk of stomach cancer. <strong>Squares</strong> indicate study-specific relative risks (<strong>size of the square</strong> reflects the study-specific statistical weight, i.e., the inverse of the variance); <strong>horizontal lines</strong> indicate 95% confidence intervals; <strong>diamond</strong> indicates summary relative risk estimate with its corresponding 95% confidence interval. Test for heterogeneity: <em>Q</em> = 19.11, <em>P</em> = .06, <em>I</em><sup>2</sup> = 42.4%. All statistical tests were two-sided.
</p>
<div class="sb-div caption-clear"></div>
</div>
</div>
<h4>Dose–response meta-analysis.</h4>
<p id="p-25">The dose–response meta-analysis of processed meat consumption included six cohort studies (<em>N</em> = 2209 cases) <em>(<a id="xref-ref-11-5" class="xref-bibr" href="#ref-11">11</a>,<a id="xref-ref-13-4" class="xref-bibr" href="#ref-13">13</a>,<a id="xref-ref-15-7" class="xref-bibr" href="#ref-15">15</a>,<a id="xref-ref-16-4" class="xref-bibr" href="#ref-16">16</a>,<a id="xref-ref-19-6" class="xref-bibr" href="#ref-19">19</a>,<a id="xref-ref-20-6" class="xref-bibr" href="#ref-20">20</a>)</em> and nine case–control studies (<em>N</em> = 2495 cases) <em>(<a id="xref-ref-21-7" class="xref-bibr" href="#ref-21">21</a>,<a id="xref-ref-25-4" class="xref-bibr" href="#ref-25">25</a>,<a id="xref-ref-29-5" class="xref-bibr" href="#ref-29">29</a>,<a id="xref-ref-33-4" class="xref-bibr" href="#ref-33">33</a>,<a id="xref-ref-35-4" class="xref-bibr" href="#ref-35">35</a>,<a id="xref-ref-37-4" class="xref-bibr" href="#ref-37">37</a>,<a id="xref-ref-39-4" class="xref-bibr" href="#ref-39">39</a>–<a id="xref-ref-41-3" class="xref-bibr" href="#ref-41">41</a>)</em>. One cohort study <em>(<a id="xref-ref-14-4" class="xref-bibr" href="#ref-14">14</a>)</em> and five case–control studies <em>(<a id="xref-ref-23-3" class="xref-bibr" href="#ref-23">23</a>,<a id="xref-ref-24-2" class="xref-bibr" href="#ref-24">24</a>,<a id="xref-ref-36-3" class="xref-bibr" href="#ref-36">36</a>,<a id="xref-ref-38-2" class="xref-bibr" href="#ref-38">38</a>,<a id="xref-ref-42-7" class="xref-bibr" href="#ref-42">42</a>)</em> were excluded because processed meat consumption could not be quantified <em>(<a id="xref-ref-14-5" class="xref-bibr" href="#ref-14">14</a>,<a id="xref-ref-24-3" class="xref-bibr" href="#ref-24">24</a>,<a id="xref-ref-38-3" class="xref-bibr" href="#ref-38">38</a>,<a id="xref-ref-42-8" class="xref-bibr" href="#ref-42">42</a>)</em> or because the range of exposure was very narrow <em>(<a id="xref-ref-23-4" class="xref-bibr" href="#ref-23">23</a>,<a id="xref-ref-36-4" class="xref-bibr" href="#ref-36">36</a>)</em>, leading to exaggerated regression coefficients.
</p>
<p id="p-26">The estimated summary relative risks of stomach cancer for an increase in processed meat consumption of 30 g/day were 1.15
(95% CI = 1.04 to 1.27) for cohort studies and 1.38 (95% CI = 1.19 to 1.60) for case–control studies. There was no statistically
significant heterogeneity among the cohort studies or among the case–control studies (<a id="xref-table-wrap-3-1" class="xref-table" href="#T3">Table 3</a>), but the estimated summary relative risk was statistically significantly higher for case–control than for cohort studies
(<em>Q</em> = 3.97; <em>P</em> = .05). The association between processed meat consumption and stomach cancer risk was similar for population-based case–control
and hospital based case–control studies (<em>Q</em> = 0.17; <em>P</em> = .68).
</p>
<div class="table pos-float" id="T3">
<div class="table-inline">
<div class="callout"><span>View this table:</span><ul class="callout-links">
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</div>
<div class="table-caption"><span class="table-label"><strong>Table 3.</strong> </span>
<p id="p-27" class="first-child">Estimated summary relative risks of stomach cancer for an increase in processed meat consumption of 30 g/day*</p>
<div class="sb-div caption-clear"></div>
</div>
</div>
<h4>Individual processed meat items.</h4>
<p id="p-30">Bacon consumption was examined in three cohort studies <em>(<a id="xref-ref-12-3" class="xref-bibr" href="#ref-12">12</a>,<a id="xref-ref-17-5" class="xref-bibr" href="#ref-17">17</a>,<a id="xref-ref-20-7" class="xref-bibr" href="#ref-20">20</a>)</em> and four case–control studies <em>(<a id="xref-ref-25-5" class="xref-bibr" href="#ref-25">25</a>,<a id="xref-ref-30-2" class="xref-bibr" href="#ref-30">30</a>,<a id="xref-ref-31-3" class="xref-bibr" href="#ref-31">31</a>,<a id="xref-ref-40-3" class="xref-bibr" href="#ref-40">40</a>)</em>. All studies reported a positive association, and in two cohort studies <em>(<a id="xref-ref-17-6" class="xref-bibr" href="#ref-17">17</a>,<a id="xref-ref-20-8" class="xref-bibr" href="#ref-20">20</a>)</em> and one case–control study <em>(<a id="xref-ref-31-4" class="xref-bibr" href="#ref-31">31</a>)</em> the relationship was statistically significant (<a id="xref-fig-3-1" class="xref-fig" href="#F3">Fig. 3</a>). There was no statistically significant heterogeneity between the summary relative risks for cohort and case–control studies
(<em>Q</em> = 0.00; <em>P</em> = .96). When all seven studies were analyzed together, the summary relative risk of stomach cancer was 1.37 (95% CI = 1.17
to 1.61) for individuals in the highest category of bacon consumption compared with those in the lowest category. There was
no statistically significant heterogeneity among the seven studies (<em>Q</em> = 4.13; <em>P</em> = .66; <em>I</em><sup>2</sup> = 0), and no publication bias was found (<em>P</em> = .51).
</p>
<div id="F3" class="fig pos-float odd">
<div class="fig-inline"><a href="1078/F3.expansion.html"><img alt="Fig. 3." src="1078/F3.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links">
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<div class="fig-caption"><span class="fig-label"><strong>Fig. 3.</strong></span>
<p id="p-31" class="first-child">Relative risks from cohort and case–control studies examining the association between bacon consumption (highest versus lowest
category) and risk of stomach cancer. <strong>Squares</strong> indicate study-specific relative risks (<strong>size of the square</strong> reflects the study-specific statistical weight, i.e., the inverse of the variance); <strong>horizontal lines</strong> indicate 95% confidence intervals; <strong>diamond</strong> indicates summary relative risk estimate with its corresponding 95% confidence interval. Test for heterogeneity: cohort studies,
<em>Q</em> = 0.35, <em>P</em> = .84, <em>I</em><sup>2 =</sup> 0; case–control studies, <em>Q</em> = 3.77, <em>P</em> = .29, <em>I</em><sup>2 =</sup> 20.4%. All statistical tests were two-sided.
</p>
<div class="sb-div caption-clear"></div>
</div>
</div>
<p id="p-32">Sausage consumption was evaluated in three cohort studies <em>(<a id="xref-ref-17-7" class="xref-bibr" href="#ref-17">17</a>,<a id="xref-ref-18-4" class="xref-bibr" href="#ref-18">18</a>,<a id="xref-ref-20-9" class="xref-bibr" href="#ref-20">20</a>)</em> and six case–control studies <em>(<a id="xref-ref-22-2" class="xref-bibr" href="#ref-22">22</a>,<a id="xref-ref-26-4" class="xref-bibr" href="#ref-26">26</a>,<a id="xref-ref-28-5" class="xref-bibr" href="#ref-28">28</a>,<a id="xref-ref-30-3" class="xref-bibr" href="#ref-30">30</a>,<a id="xref-ref-31-5" class="xref-bibr" href="#ref-31">31</a>,<a id="xref-ref-41-4" class="xref-bibr" href="#ref-41">41</a>)</em>. Three case–control studies reported a statistically significant positive association between sausage consumption and stomach
cancer risk <em>(<a id="xref-ref-26-5" class="xref-bibr" href="#ref-26">26</a>,<a id="xref-ref-28-6" class="xref-bibr" href="#ref-28">28</a>,<a id="xref-ref-31-6" class="xref-bibr" href="#ref-31">31</a>)</em>, and two case–control <em>(<a id="xref-ref-22-3" class="xref-bibr" href="#ref-22">22</a>,<a id="xref-ref-41-5" class="xref-bibr" href="#ref-41">41</a>)</em> and two cohort studies <em>(<a id="xref-ref-18-5" class="xref-bibr" href="#ref-18">18</a>,<a id="xref-ref-20-10" class="xref-bibr" href="#ref-20">20</a>)</em> found non–statistically significant increased risks (<a id="xref-fig-4-1" class="xref-fig" href="#F4">Fig. 4</a>). There was no statistically significant heterogeneity between the summary relative risks for cohort and case–control studies
(<em>Q</em> = 0.58; <em>P</em> = .45). Analysis of all nine studies showed a summary relative risk of 1.39 (95% CI = 1.12 to 1.73) for high versus low sausage
consumption; however, there was statistically significant heterogeneity among studies (<em>Q</em> = 19.52; <em>P</em> = .01; <em>I</em><sup>2</sup> = 59.0%). Publication bias was observed for all studies (<em>P</em> =.03) but not by study type (<em>P</em> = .41 for cohort studies and <em>P</em> = .11 for case–control studies).
</p>
<div id="F4" class="fig pos-float odd">
<div class="fig-inline"><a href="1078/F4.expansion.html"><img alt="Fig. 4." src="1078/F4.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links">
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<div class="fig-caption"><span class="fig-label"><strong>Fig. 4.</strong></span>
<p id="p-33" class="first-child">Relative risks from cohort and case–control studies examining the association between sausage consumption (highest versus
lowest category) and risk of stomach cancer. <strong>Squares</strong> indicate study-specific relative risks (<strong>size of the square</strong> reflects the study-specific statistical weight, i.e., the inverse of the variance); <strong>horizontal lines</strong> indicate 95% confidence intervals; <strong>diamond</strong> indicates summary relative risk estimate with its corresponding 95% confidence interval. Test for heterogeneity: cohort studies,
<em>Q</em> = 3.65, <em>P</em> = .16, <em>I</em><sup>2 =</sup> 45.3%; case–control studies, <em>Q</em> = 15.21, <em>P</em> = .01, <em>I</em><sup>2 =</sup> 67.1%. All statistical tests were two-sided.
</p>
<div class="sb-div caption-clear"></div>
</div>
</div>
<p id="p-34">Ham consumption was investigated in two cohort studies <em>(<a id="xref-ref-17-8" class="xref-bibr" href="#ref-17">17</a>,<a id="xref-ref-20-11" class="xref-bibr" href="#ref-20">20</a>)</em> and three case–control studies <em>(<a id="xref-ref-22-4" class="xref-bibr" href="#ref-22">22</a>,<a id="xref-ref-25-6" class="xref-bibr" href="#ref-25">25</a>,<a id="xref-ref-31-7" class="xref-bibr" href="#ref-31">31</a>)</em>. Of the two cohort studies, one observed a non–statistically significant 48% (RR = 1.48; 95% CI = 0.99 to 2.22) increased
risk of stomach cancer for high versus low ham consumption <em>(<a id="xref-ref-20-12" class="xref-bibr" href="#ref-20">20</a>)</em>, whereas the other cohort study <em>(<a id="xref-ref-17-9" class="xref-bibr" href="#ref-17">17</a>)</em> did not support such an association (RR = 0.77; 95% CI = 0.56 to 1.07). In the three case–control studies, there was a statistically
significant 64% increased risk of stomach cancer for individuals in the highest relative to the lowest category of ham consumption
(RR = 1.64, 95% CI = 1.31 to 2.06; <a id="xref-fig-5-1" class="xref-fig" href="#F5">Fig. 5</a>). The Egger's test of publication bias for case–control studies was of borderline statistical significance (<em>P</em> = .10).
</p>
<div id="F5" class="fig pos-float odd">
<div class="fig-inline"><a href="1078/F5.expansion.html"><img alt="Fig. 5." src="1078/F5.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links">
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<div class="fig-caption"><span class="fig-label"><strong>Fig. 5.</strong></span>
<p id="p-35" class="first-child">Relative risks from case–control studies examining the association between ham consumption (highest versus lowest category)
and risk of stomach cancer. <strong>Squares</strong> indicate study-specific relative risks (<strong>size of the square</strong> reflects the study-specific statistical weight, i.e., the inverse of the variance); <strong>horizontal lines</strong> indicate 95% confidence intervals; <strong>diamond</strong> indicates summary relative risk estimate with its corresponding 95% confidence interval. Test for heterogeneity: <em>Q</em> = 0.19, <em>P</em> = .91, <em>I</em><sup>2 =</sup> 0. All statistical tests were two-sided.
</p>
<div class="sb-div caption-clear"></div>
</div>
</div>
</div>
<div class="section" id="sec-12">
<div class="section-nav"><a href="#sec-6" title="RESULTS" class="prev-section-link"><span>Previous Section</span></a><a href="#fn-group-1" title="Footnotes" class="next-section-link"><span>Next Section</span></a></div>
<h2>D<span class="sc">ISCUSSION</span></h2>
<p id="p-36">Findings of this meta-analysis support a positive relationship between processed meat consumption and risk of stomach cancer.
Overall, an increase in processed meat consumption of 30 g/day was associated with statistically significant 15% and 38% increased
risks of stomach cancer in cohort studies and case–control studies, respectively. Among the individual processed meat items,
findings were most consistent for bacon consumption. Summary results indicate that there was a statistically significant 37%
higher risk of stomach cancer among those in the highest relative to the lowest category of bacon consumption.
</p>
<p id="p-37">Our study has several limitations. First, as a meta-analysis of observational studies, it is prone to bias (e.g., recall and
selection bias) inherent in the original studies. Prospective cohort studies are less susceptible to bias than case–control
studies because, in the prospective design, information on exposures is collected before the diagnosis of the disease. The
association between processed meat consumption and stomach cancer risk was statistically significantly stronger in the case–control
studies than in the cohort studies. It is possible that the relationships reported from case–control studies may have been
overstated due to recall or interviewer bias and possible prediagnostic early symptoms in cancer patients may have led to
changes in dietary habits. Moreover, selection bias is of concern in the studies with low participation rates among control
subjects <em>(<a id="xref-ref-21-8" class="xref-bibr" href="#ref-21">21</a>,<a id="xref-ref-29-7" class="xref-bibr" href="#ref-29">29</a>,<a id="xref-ref-40-4" class="xref-bibr" href="#ref-40">40</a>)</em> because those who participate are likely to be more health conscious and thus might consume less meat than nonrespondents.
</p>
<p id="p-38">A second limitation is that individual studies may have failed to control for potential confounders, which may introduce bias
in an unpredictable direction. For example, infection with <em>H. pylori</em> is an established risk factor for gastric noncardia cancer <em>(<a id="xref-ref-3-2" class="xref-bibr" href="#ref-3">3</a>)</em>. No study controlled for <em>H. pylori</em> infection status, although one study <em>(<a id="xref-ref-19-7" class="xref-bibr" href="#ref-19">19</a>)</em> examined whether the association between processed meat consumption and stomach cancer risk was modified by <em>H. pylori</em> infection (see below). The two prospective studies that showed a statistically significant increased risk of stomach cancer
associated with a high consumption of processed meat <em>(<a id="xref-ref-19-8" class="xref-bibr" href="#ref-19">19</a>,<a id="xref-ref-20-13" class="xref-bibr" href="#ref-20">20</a>)</em> both adjusted for major potential confounders, such as age, education, smoking, body size, and intakes of total energy, alcohol,
fruits, and vegetables. In these studies, the age-adjusted relative risks for the highest compared with the lowest category
of processed meat consumption [RR = 1.58, 95% CI = 1.09 to 2.29 <em>(<a id="xref-ref-19-9" class="xref-bibr" href="#ref-19">19</a>)</em> and RR = 1.69, 95% CI = 1.17 to 2.45 <em>(<a id="xref-ref-20-14" class="xref-bibr" href="#ref-20">20</a>)</em>, respectively] were similar to the multivariable relative risks [RR = 1.62, 95% CI = 1.08 to 2.41 <em>(<a id="xref-ref-19-10" class="xref-bibr" href="#ref-19">19</a>)</em> and RR = 1.66, 95% CI = 1.13 to 2.45 <em>(<a id="xref-ref-20-15" class="xref-bibr" href="#ref-20">20</a>)</em>, respectively], indicating a lack of confounding from the considered covariates. Of the case–control studies, only approximately
half controlled for age, sex, and education (or socioeconomic status) <em>(<a id="xref-ref-22-5" class="xref-bibr" href="#ref-22">22</a>,<a id="xref-ref-26-6" class="xref-bibr" href="#ref-26">26</a>,<a id="xref-ref-30-4" class="xref-bibr" href="#ref-30">30</a>,<a id="xref-ref-35-5" class="xref-bibr" href="#ref-35">35</a>,<a id="xref-ref-38-4" class="xref-bibr" href="#ref-38">38</a>,<a id="xref-ref-40-5" class="xref-bibr" href="#ref-40">40</a>–<a id="xref-ref-42-9" class="xref-bibr" href="#ref-42">42</a>)</em> or for smoking <em>(<a id="xref-ref-29-8" class="xref-bibr" href="#ref-29">29</a>,<a id="xref-ref-35-6" class="xref-bibr" href="#ref-35">35</a>–<a id="xref-ref-41-6" class="xref-bibr" href="#ref-41">41</a>),</em> and only four adjusted for fruit and vegetable consumption <em>(<a id="xref-ref-22-6" class="xref-bibr" href="#ref-22">22</a>,<a id="xref-ref-23-5" class="xref-bibr" href="#ref-23">23</a>,<a id="xref-ref-25-7" class="xref-bibr" href="#ref-25">25</a>,<a id="xref-ref-40-6" class="xref-bibr" href="#ref-40">40</a>)</em>. Hence, the possibility of confounding from unaccounted nondietary and dietary risk factors for stomach cancer cannot be
excluded.
</p>
<p id="p-39">A third limitation is that our results were likely to be affected by imprecise measurement of processed meat consumption and
of potential confounders in the original studies. Categorization of main exposures and confounders that are measured with
nondifferential error (independent of disease status) may induce differential misclassification and may bias the expected
relative risk toward or away from the null value <em>(<a id="xref-ref-50-1" class="xref-bibr" href="#ref-50">50</a>–<a id="xref-ref-52-1" class="xref-bibr" href="#ref-52">52</a>)</em>. Thus, misclassification of processed meat consumption and of potential confounders in the studies included in this meta-analysis
might have led to an overestimate or an underestimate of the summary relative risks.
</p>
<p id="p-40">A fourth limitation is that the consumption levels in the lowest and highest categories and the range of consumption varied
across studies. These differences may have contributed to the heterogeneity among studies in the analysis of the highest versus
the lowest intake categories. To account for the different ranges of processed meat consumption, we estimated for each study
(that provided the required data) a relative risk for an increase in intake of 30 g/day.
</p>
<p id="p-41">Finally, as with any meta-analysis, possible publication bias is of concern. Only studies of sausage consumption showed statistically
significant publication bias. Thus, the summary results may be an overestimate of the relative risk of stomach cancer associated
with sausage consumption.
</p>
<p id="p-42">A positive relationship between processed meat consumption and risk of stomach cancer is biologically plausible. In addition
to having high amounts of salt, processed meat often contains nitrite or nitrate and <em>N</em>-nitroso compounds <em>(<a id="xref-ref-7-2" class="xref-bibr" href="#ref-7">7</a>–<a id="xref-ref-9-2" class="xref-bibr" href="#ref-9">9</a>). N</em>-Nitroso compounds are potent carcinogens that can induce tumors in various animal species at several sites <em>(<a id="xref-ref-7-3" class="xref-bibr" href="#ref-7">7</a>,<a id="xref-ref-53-1" class="xref-bibr" href="#ref-53">53</a>). N</em>-Nitroso compounds are also formed endogenously in the stomach through nitrosation by nitrites of amines or amides. Sugimura
and Fujimura <em>(<a id="xref-ref-54-1" class="xref-bibr" href="#ref-54">54</a>)</em> showed that gastric carcinomas were induced in rats in response to oral administration of an <em>N</em>-nitroso compound, <em>N</em>-methyl-<em>N</em>′-nitro-<em>N</em>-nitrosoguanidine. Furthermore, several epidemiologic studies have reported a statistically significant positive association
between <em>N</em>-nitrosodimethylamine or nitrosamine intake with stomach cancer risk <em>(<a id="xref-ref-20-16" class="xref-bibr" href="#ref-20">20</a>,<a id="xref-ref-55-1" class="xref-bibr" href="#ref-55">55</a>–<a id="xref-ref-58-1" class="xref-bibr" href="#ref-58">58</a>)</em>. Although salt is not intrinsically carcinogenic, it may act as an irritant to the gastric mucosa, leading to gastritis,
increased DNA synthesis, and cell proliferation <em>(<a id="xref-ref-4-2" class="xref-bibr" href="#ref-4">4</a>–<a id="xref-ref-6-2" class="xref-bibr" href="#ref-6">6</a>)</em>. Excess salt also makes the mucosa cells more susceptible to carcinogens from foods. In experimental studies with rats, salt
enhances the carcinogenic effects of gastric carcinogens, such as the <em>N</em>-nitroso compound <em>N</em>-methyl-<em>N</em>′-nitro-<em>N</em>-nitrosoguanidine <em>(<a id="xref-ref-59-1" class="xref-bibr" href="#ref-59">59</a>–<a id="xref-ref-61-1" class="xref-bibr" href="#ref-61">61</a>)</em>.
</p>
<p id="p-43">It is possible that the relationship between processed meat consumption and stomach cancer risk is restricted to certain subgroups
of the population, such as those with specific genetic polymorphisms coding for enzymes involved in the metabolism of <em>N</em>-nitroso compounds or those infected with <em>H. pylori</em>. In a nested case–control study within the European Prospective Investigation Into Cancer and Nutrition <em>(<a id="xref-ref-19-11" class="xref-bibr" href="#ref-19">19</a>)</em>, the positive association between processed meat consumption and stomach cancer risk appeared to be restricted to <em>H. pylori</em> antibody–positive subjects. An association with processed meat consumption may also be modified by intake of vitamins C and
E, fruits, and vegetables because these dietary factors can reduce the formation of <em>N</em>-nitroso compounds in the stomach <em>(<a id="xref-ref-62-1" class="xref-bibr" href="#ref-62">62</a>)</em>. In the Swedish Mammography Cohort <em>(<a id="xref-ref-20-17" class="xref-bibr" href="#ref-20">20</a>)</em>, the positive association of processed meat consumption with stomach cancer risk was somewhat stronger among women with a
low consumption of fruits and vegetables.
</p>
<p id="p-44">Four studies investigated whether the association between processed meat <em>(<a id="xref-ref-19-12" class="xref-bibr" href="#ref-19">19</a>,<a id="xref-ref-35-7" class="xref-bibr" href="#ref-35">35</a>,<a id="xref-ref-39-5" class="xref-bibr" href="#ref-39">39</a>)</em> or sausage <em>(<a id="xref-ref-26-7" class="xref-bibr" href="#ref-26">26</a>)</em> consumption and stomach cancer risk differed by histological subtype (intestinal versus diffuse); none showed any appreciable
difference. In the only study that examined risk by anatomical subsite, high consumption of processed meat was associated
with an increased risk of gastric noncardia cancer (highest versus lowest intake category, RR = 1.92; 95% CI = 1.11 to 3.33)
but not of gastric cardia cancer (highest versus lowest intake category, RR = 1.14; 95% CI = 0.52 to 2.49) <em>(<a id="xref-ref-19-13" class="xref-bibr" href="#ref-19">19</a>)</em>.
</p>
<p id="p-45">In summary, findings of this meta-analysis support the hypothesis that high consumption of processed meat may be associated
with an increased risk of stomach cancer. Future studies should control for more potential confounders and examine whether
the association between processed meat consumption and stomach cancer risk is modified by other dietary factors, <em>H. pylori</em> infection status, or genetic polymorphisms. In addition, whether the association differs according to histologic subtype
or anatomic subsite warrants further study.
</p>
</div>
<div class="section fn-group" id="fn-group-1">
<div class="section-nav"><a href="#sec-12" title="DISCUSSION" class="prev-section-link"><span>Previous Section</span></a><a href="#ref-list-1" title="References" class="next-section-link"><span>Next Section</span></a></div>
<h2>Footnotes</h2>
<ul>
<li class="fn" id="fn-8">
<p id="p-46">This study was supported by research grants from the Swedish Cancer Society (A. Wolk) and the Swedish Research Council/Longitudinal
Studies (A. Wolk). The study sponsors had no role in the design, collection, analysis, or interpretation of the data, or in
the writing or decision to submit the manuscript.
</p>
</li>
</ul>
</div>
<ul>
<li class="fn" id="copyright-statement-1">© The Author 2006. Published by Oxford University Press.</li>
</ul>
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<div class="section-nav"><a href="#fn-group-1" title="Footnotes" class="prev-section-link"><span>Previous Section</span></a><div class="nav-placeholder"> </div>
</div>
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