Werner syndrome study population.

*<p>ns = not specified or reported.</p>**<p>among patients whose age at diagnosis is specified.</p>***<p>number of patients by WS diagnostic confidence: definite (n = 50), probable (n = 35), possible (n = 22), and unknown (n = 32).</p>****<p>number of patients by WS diagnostic confidence: definite (n = 22), probable (n = 13), possible (n = 10), and unknown (n = 5).</p

Standardized proportionate incidence ratios (SPIRs) for malignancies in Japan-resident Werner syndrome patients.

*<p>statistically significant result (p<0.05).</p>**<p>includes WS patients with high WS diagnostic confidence (1965–2009, ages 10–69). Includes benign meningiomas diagnosed prior to 1988, but excludes non-melanoma skin neoplasms.</p>***<p>obtained using Osaka, Japan <i>CI5</i> volume case data (i.e., representative sample from 1970–2002).</p

Median ages and age ranges for cancer in Werner syndrome versus other cancer predisposition syndromes.

*<p>malignant cases only, except for meningiomas where benign cases were also included.</p>**<p>Japan-residents cases only, excluding tumor cases with ambiguous age at diagnosis.</p>***<p>BS = Bloom syndrome. Some discrepancies between data given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059709#pone-0059709-g002" target="_blank">Figure 2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059709#pone-0059709-t004" target="_blank">Table 4</a> of reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059709#pone.0059709-German1" target="_blank">[23]</a>.</p>****<p>RTS = Rothmund-Thomson syndrome <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059709#pone.0059709-Siitonen1" target="_blank">[25]</a>. Note that adding 6 additional tumor cases reported in patients with RAPADILINO syndrome, which is also caused by mutations in <i>RecQL4</i>, has minimal effect (all sites estimate becomes 13 (2, 33)).</p>*****<p>Osaka population ages given by 5-year age groups, so medians are approximate. Data obtained from <i>CI5</i>plus online application (years 1963–2002); soft tissue and all sites data from <i>CI5</i> volumes 3–9 (years 1970–2002) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059709#pone.0059709-Ferlay1" target="_blank">[7]</a>. SEER data from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059709#pone.0059709-Howlader1" target="_blank">[35]</a>.</p><p>na = not accessed.</p

Spectrum of neoplasia in Werner syndrome patients.

<p>Distribution of neoplasms by histopathologic type and frequency among study population subjects included in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059709#pone.0059709.s003" target="_blank">Table S1</a>.</p

Werner syndrome diagnostic criteria.

*<p>WS signs and symptoms are from the diagnostic criteria established by the International Registry of Werner Syndrome: <a href="http://www.wernersyndrome.org/registry/diagnostic.html" target="_blank">www.wernersyndrome.org/registry/diagnostic.html</a>.</p>**<p>Reported cataracts were assumed bilateral if not explicitly stated, and characteristic dermatological pathology was considered to be present if any one of the six skin pathologies was reported, again as defined by the Werner Syndrome Registry diagnostic signs and symptoms list. Where height was not designated as ‘short stature’, we classified males with heights <164 cm and females with heights <154 cm as of short stature. Diabetes mellitus was considered present if a diagnosis of diabetes and/or evidence of abnormal glucose homeostasis was provided.</p

Werner syndrome diagnostic confidence categories.

<p> <b><i>Diagnostic criteria and categorization notes:</i></b></p>*<p>WS diagnostic confidence categories were taken from the International Registry of Werner Syndrome: <a href="http://www.wernersyndrome.org/registry/diagnostic.html" target="_blank">www.wernersyndrome.org/registry/diagnostic.html</a> with the following modifications: 1. putative WS patients with known pathogenic mutations in both <i>WRN</i> alleles were also considered to be ‘Definite’/‘High confidence’; and 2. “mesenchymal neoplasms, rare neoplasms or multiple neoplasm” was not counted for any of the patients in the determination of Werner syndrome diagnostic confidence.</p>**<p>We had no case exclusions based on the onset of signs or symptoms prior to adolescence. Two Japan-resident cases were reported with voice changes prior to adolescence, and one Japan non-resident case was reported to have had premature greying of the hair at age 8 (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059709#pone.0059709.s003" target="_blank">Table S1</a>).</p

Standardized incidence ratios (SIRs) for malignancies in Japan-resident Werner syndrome patients.^***

*<p>statistically significant result (p<0.05).</p>**<p>includes benign meningiomas diagnosed prior to 1988, but excludes non-melanoma skin neoplasms.</p>***<p>for patients with high WS diagnostic confidence (1965–2009).</p>****<p>relative to Osaka, Japan population, 1965–2009.</p><p><b>note:</b> analysis conditioned on a <i>WRN</i> pathogenic allele frequency of <i>q = 0.0037.</i></p

Cumulative percentage of malignancies (%) by age at diagnosis in Japan-resident WS cases (1965–2009) versus Osaka population (1998–2002).

<p>*Osaka prefecture neoplasm-specific population incidence data were categorized by gender and aggregated into 5-year age groups. Hence we were able to calculate only a median age range from Osaka population data, in contrast to the exact median age we were able to calculate for our WS patient cohort.</p

Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of esophageal adenocarcinoma among cigarette smokers in the SBES cohort.

†<p>– Age modeled as a continuous variable,</p>‡<p>– WHR modeled as a continuous variable,</p>¶<p>– NSAID use modeled as a categorical variable (Current, Former, never).</p><p>T1: Tertile 1, T2: Tertile 2, T3: Tertile 3.</p>*<p>Test for trend was based on the likelihood-ratio test associated with addition of the variable under consideration in its continuous form.</p

Anthropometric measurements of all participants in the SBES cohort at baseline.

†<p>Two males had missing waist and hip circumferences at baseline.</p><p>Q1: Quartile 1, Q2: Quartile 2, Q3: Quartile 3, Q4: Quartile 4.</p><p>Waist-Hip ratio- Entire cohort: Q1 0.72-, Q2 0.91-, Q3 0.95-, Q4 0.99-; Males: Q1 0.72-, Q2 0.93-, Q3 0.96-, Q4 1.00-; Females: Q1 0.72-, Q2 0.81-, Q3 0.87-, Q4 0.91-.</p><p>Waist circumference – Entire chort: Q1 25.5-, Q2 37.1-, Q3 39.6-, Q4 42.5-; Males: Q1 25.5-, Q2 37.6-, Q3 39.8-, Q4 42.6-; Females: Q1 25.5-, Q2 33.5-, Q3 37.9-, Q4 40.8-.</p><p>Hip circumference - Entire chort: Q1 32.0-, Q2 39.5-, Q3 41.7-, Q4 43.9-; Males: Q1 32.0-, Q2 39.6-, Q3 41.7-, Q4 43.4-; Females: Q1 32.0-, Q2 39.0-, Q3 41.8-, Q4 40.8-.</p