Longevity and pleural mesothelioma: age-period-cohort analysis of incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program, 1973–2013
Kerger BMC Res Notes
Longevity and?pleural mesothelioma: age-period-cohort analysis of?incidence data from?the?Surveillance, Epidemiology, and?End Results (SEER) Program, 1973-2013
Brent D. Kerger 0
0 Exponent Inc. , 15615 Alton Parkway, Suite 350, Irvine, CA 92618 , USA
Objective: This study investigates the hypothesis that an increasing fraction of incident pleural mesothelioma (PM) in the US population may be related to longevity, i.e., to expansion of the population over age 75 years with an agerelated elevation in risk. An age-period-cohort analysis of the SEER 9 cancer registries (1973-2013) was conducted using 5-year intervals of age, calendar period, and birth cohort after stratification into four gender-age groups (male and female; 0-74 and 75+ years). Results: Gender-specific time trends in age-adjusted PM incidence by age groups were observed. After adjusting for cohort effects, males in the 0-74-year age group experienced rapidly declining PM incidence rates following the observed peak in 1978-1982, whereas continuously increasing incidence rates were observed among older males. A significant cohort effect was also observed among males in both age groups, with peak incidence rates in the 1926-1930/1928-1932 birth cohorts and thereafter. The distinct period and cohort effects among males age 0-74 years may be driven by declining age-adjusted PM incidence rates corresponding to the decline in occupational asbestos exposures post-World War II, whereas the increasing time trend seen in both genders at age 75+ may reflect an increasing proportion due to longevity-related factors.
Epidemiology; Cohort effect; Period effect; Age effect; Age distribution; Asbestos; World War II era
The commonly considered etiology of malignant pleural
mesothelioma (PM) is occupational asbestos exposure;
however, the disease can also arise due to exposures to
erionite, non-commercial amphiboles, or ionizing
radiation, and from genetic predisposition or spontaneous
]. In the past three decades, PM incidence
data from the SEER program revealed a peak male
ageadjusted rate occurring in the early 1990s and a
subsequent decline [
]; the decline was more pronounced
among males age 0?74 [
3, 5, 6
]. The SEER 9 data also
reveal an increasing proportion of PM among age 75+
males and females since the early 1990s (Fig.? 1). The
age-adjusted PM decline among age 0?74 males may
relate to increasingly stringent US regulations on
asbestos use that were put into place starting in the 1970s.
Logically, a fraction of PM incidence at age 75+ must
be attributable to decades-prior occupational asbestos
exposures among longevity-prone individuals. However,
recent reports have identified increased age-adjusted PM
incidence for age 75+ males and females [
questions about what fraction occurred spontaneously
or from non-asbestos causes. Using linear spline
analysis for the SEER 9 data through 2012, Beckerman et? al.
 reported that PM incidence among males age 0?74
is predicted to intersect the rate for age 0?74 females
within the next decade.
Dramatic changes in the actual and predicted
age distribution of the US population have been
Fig. 1 Pleural mesothelioma counts stratified by age (0?74, 75+ years old) among US males (a) and females (b). Darker portion of each bar
corresponds to ages 0?74 years and lighter portion to 75+ years. Based on annual incidence data from the SEER 9 registry collected from 1973 to
documented in the past three decades, concurrent
with the rise in age-adjusted PM incidence for age 75+
males and females (Fig.?2). Based on census data [
the number of individuals in the US population living
beyond age 75 has more than doubled between 1973
and 2012. Because of elevated birth rates in the US
between 1946 and 1964 (the so-called ?baby boomer
generation?) and increased longevity, the number of
individuals surviving beyond age 75 is predicted to
more than double again between 2012 and 2050 [
Accordingly, longevity-related changes are expected to
become increasingly important influences on the
incidence of PM and other late-life cancers [
It is hypothesized that some of the continued
elevation in PM in more elderly individuals (i.e., the 75+
age group) may be due to age-related factors in this
growing population subset. This hypothesis is
investigated by conducting an age-period-cohort analysis of
males and females age 0?74 and age 75+ within the
SEER 9 cancer registries (1973?2013).
The incidence data for primary malignant pleural
mesothelioma (International Classification of Diseases for
Oncology, 3rd edition, histology codes 9050-9055, sites
C38.4 and C38.8) was obtained from the US Surveillance,
Epidemiology, and End Results (SEER) 9
populationbased cancer registries from 1973 to 2013. Data were
extracted by 5-year age and calendar-year groups; due to
the need for evenly grouped categories (e.g., 1973?1977,
1978?1982 ? 2008?2012), the year 2013 was
omitted from period analyses. All analyses were stratified by
selected age category (0?74 or 75+ years) and sex (male
or female). Data were accessed using SEER*Stat software
version 8.3.2 after execution of the SEER data use
agreement which includes compliance with ethical and privacy
considerations and allows use of the cancer incidence
data without separate requirements for study subject
consent or Institutional Review Board approval.
The National Cancer Institute (NCI) web tool for
ageperiod-cohort (APC) analysis was applied as described
by Rosenberg et? al. [
]. The NCI APC web tool
enables analysis of net drift (annual percentage change in
the expected age-adjusted rates over time), local drifts
(annual percentage change in the expected age-specific
rates over time), fitted temporal trends (expected rates
over time in the reference age group, adjusted for cohort
effects), cross-sectional age curve (expected age-specific
rates in the reference calendar period, adjusted for cohort
effects), longitudinal age curve (expected age-specific
rates in the reference birth cohort, adjusted for period
effects), period rate ratios (ratio of age-specific rates in
each calendar period relative to the reference period),
and cohort rate ratios (ratio of age-specific rates in each
birth cohort relative to the reference cohort). The NCI
APC web tool also enables statistical testing of several
null hypotheses related to the stability, log-linearity, and
equality of observed trends. Default reference groups
were used for comparisons, i.e., the median calendar
period (1988?1992) and the median birth cohorts (1931?
1935 for ages 0?74; 1906?1910 for ages 75+).
The age categories of 0?74 and 75+ years were selected
based on demographics pertaining to post-retirement
longevity and age-related PM trends associated with
occupational asbestos exposure. First, age 75+ can be
considered an ?old age? category, given that it is
approximately a decade beyond the common retirement age
(between 62 and 67? years) for US workers during the
1990s and 2000s. Second, the peak age-specific
incidence and mortality from PM in the US is estimated to be
between ages 70 and 80 [
]; age 75 represents a median
point higher than the mean age at PM death in the US
(72.8 ? 11.1?years) and worldwide (70.1 ? 11?years) based
on data from 1994 to 2008 [
]. Third, among German
asbestos workers the mean age at mesothelioma
diagnosis was 60.4 ? 9.9? years and mean age at mesothelioma
death was 63.6 ? 10.7?years in 1987?1999 [
indicates that the vast majority of cases due to occupational
asbestos exposure occurred in the 0?74 age category.
Similar findings for PM death within the 0?74 age range
were reported for US insulation workers [
Key findings of the APC analysis for PM in the four age/
gender groups are summarized in Table? 1. The period
effect after adjustment for birth cohort effects revealed
similar peak PM incidence years according to age group:
younger females showed a peak value in 1973?1977 and
younger males peaked slightly later in 1978?1982; older
males and females both showed peak incidence in the
most recent 5-year time period (2008?2012) (Table? 1;
Additional file? 1: Figure S1). Net drift values
indicated significant decreasing time trends in age-adjusted
PM incidence for age 0?74 males but not for age 0?74
females, while increasing net drift trends were found for
males and females age 75 + (Table? 1). Period rate ratios
(in comparison with the reference period of 1988?1992)
were significantly different from 1.0 for all groups except
age 0?74 females (Table?1). Analysis of period deviations
indicated significant non-linear trends for males of both
age groups, but no significant deviation from
log-linearity for females (Table?1).
The birth cohort effect after adjustment for period
effects revealed that peak PM incidence occurred in
comparable birth cohort years for both genders according
to age group. Age 0?74 females showed peak PM
incidence in the 1931?1935 birth cohort, just after the peak
(1928?1932 birth cohort) for age 0?74 males. Age 75+
females showed a peak PM incidence in the 1921?1925
birth cohort, just prior to the peak (1926?1930) for age
75+ males (Table?1; Additional file?2: Figure S2). Net drift
(age-adjusted time trend) was not significantly different
from local drift (age-specific time trend) in any group
except age 75+ females (Table?1). Cohort rate ratios were
significantly different from 1.0 in comparison with the
reference group (1931?1935 for ages 0?74; 1906?1910
for ages 75+), and cohort deviations indicated significant
non-linearity, except among age 0?74 females, for whom
no significant cohort effect was detected (Table?1).
Analysis of age effects on PM incidence after
adjustment for period or birth cohort effects was accomplished
by examining cross-sectional and longitudinal age trends.
Both age effects were stronger for age 0?74 males
(crosssectional age trend 12.5%; longitudinal age trend 10.7%)
than for females (7.2 and 8.7%, respectively), whereas a
slight positive or no significant age effect was observed
among age 75+ males (2.2% and ? 1.7%, respectively) and
females (? 0.1 and ? 3.7%, respectively). Distinct negative
trends consistent with a negative net drift were observed
in the longitudinal versus cross-sectional rate ratio
analysis for age 0?74 groups in both genders, whereas positive
trends consistent with a positive net drift were observed
for both genders at age 75+ (Additional file? 3: Figure
S3). Analysis of age deviations revealed significant
nonlinearity in age 75+ males and marginally significant
(p = 0.07) non-linearity for age 75+ females, but no
significant non-linearity in the age 0?74 groups (Table?1).
This APC analysis of US SEER 9 cancer registry data
from 1973 to 2013 demonstrates significant age,
period, and birth cohort effects consistent with
longevity-related factors since the early 1990s playing a
progressively more important role in PM incidence
among US males and females (Fig.? 1). Analysis of four
age-gender groups revealed distinct trends in PM
incidence between males and females age 0?74 or age 75+
that are masked beneath the total age-adjusted PM
incidence among US males, which has declined
considerably since the early 1990s [
Most notable are gender-specific differences in age,
period, and cohort trends potentially associated with
the much higher frequency of occupational/military
asbestos exposures expected for males. Specifically,
the results revealed that PM incidence in the 0?74 age
group has declined since the early 1990s for males,
whereas it has increased for both genders in the 75+
age group (Additional file? 3: Figure S3). The birth
cohorts corresponding to peak PM incidence were
nearly identical for males age 0?74 (1928?1932 birth
cohort) and age 75+ (1926?1930 birth cohort), while
the peak for females age 0?74 (1931?1935 birth cohort)
was 10? years later than that for age 75 + (1921?1925
birth cohort), as shown in Additional file?2: Figure S2.
Moreover, the analysis of period effects showed that
peak PM incidence for age 0?74 males (1978?1982)
occurred just after that for females of the same age
(1973?1977), whereas the age 75+ males and females
both showed gradually increasing PM incidence with a
peak in the most recent 5-year period (Additional file?1:
Figure S1). Thus, the 1992 peak in total age-adjusted
PM incidence among US males previously observed
in other analyses resulted from the superposition of
the gradual increase in older males (age 75+) and the
declining trend since 1978?1982 among younger males
(age 0?74). The common birth cohort for peak PM
incidence in males of both age groups (but not in females)
is consistent with a prominent influence of
occupational/military asbestos exposures during the World
War II era (i.e., 1940?1950) on male PM incidence
trends. The fraction of female PM incidence
attributable to World War II era occupational or
para-occupational asbestos exposures is unknown, but the low
magnitude and relatively flat total incidence trends over
the past four decades suggest a limited impact. Further,
the earlier period effect peak among age 75+ females
and the parallel increasing trends in age-adjusted PM
incidence for both genders suggest that other factors
relating to longevity may better explain these trends for
Overall, our findings are consistent with those of
European studies where the temporal and birth cohort
trends have been linked to periods of peak
occupational asbestos exposure and consumption surrounding
World War II and subsequent rebuilding (see
Additional file? 4: Additional discussion). These studies
collectively suggest a plausible impact of longevity-related
factors on PM incidence which should be considered
when projecting future PM rates attributable to
occupational asbestos exposures and other known causes
and risk factors.
The primary limitation of this study is the lack of direct
linkage data for assessing individual risk of PM related
known causes (e.g., exposures to asbestos, erionite, or
radiation) versus more general longevity-related factors
(e.g., aging, spontaneous disease occurrence, and
misclassification or enhanced detection). Some of the
agegender-time categories analyzed may have been too small
to provide statistically stable APC results, particularly in
regards to the lower PM incidence among females.
Additional file?1: Figure S1. Graphic presentation of APC data illustrating
the period effect after adjustment for birth cohort effects on PM incidence
in SEER 9 registries (1973?2013) in males age 0?74 (Panel A), males age
75+ (Panel B), females age 0?74 (Panel C) and females age 75+ (Panel D).
Rate ratios significantly different from 1.0 were identified for A (p < 0.0001),
B (p < 0.0001), and D (p = 0.02), but not for C (p = 0.67). Period deviations
indicate significant non-linearity for A and B, but not for C and D.
Additional file?2: Figure S2. Graphic presentation of APC data illustrating
the cohort effect after adjustment for period effects on PM incidence in
SEER 9 registries (1973?2013) in males age 0?74 (Panel A), males age 75+
(Panel B), females age 0?74 (Panel C) and females age 75+ (Panel D). Rate
ratios significantly different from 1.0 were identified for A (p < 0.0001), B
(p < 0.0001), and D (p = 0.01), but not for C (p = 0.16). Cohort deviations
indicate significant non-linearity for A, B, and D, but not for C.
Additional file?3: Figure S3. Graphic presentation of APC data
illustrating the longitudinal versus cross-sectional age effect on PM incidence
in SEER 9 registries (1973?2013) in males age 0?74 (Panel A), males age
75+ (Panel B), females age 0?74 (Panel C) and females age 75+ (Panel D).
Changes in net drift are consistent with the opposing slopes for the age
0?74 (negative) versus age 75+ (positive) rate ratios.
Additional file?4: Additional discussion. Further detailed interpretation
of relevant scientific literature that was beyond the length limitations for
the main manuscript.
APC: age-period-cohort; NCI: National Cancer Institute; PM: pleural mesothelioma;
SEER: Surveillance, Epidemiology, and End Results Program; US: United States.
BDK designed the study, analyzed the data and produced the tables and
figures in conjunction with the acknowledged statisticians below, drafted the
original manuscript and finalized it after considering peer review comments of
those acknowledged. The author read and approved the final manuscript.
The author would like to thank Ellen Chang and Gabor Mezei for their
assistance with the statistical analyses, table and figure preparation, and peer
review of the draft manuscript. The author would also like to thank Jane Teta
for her helpful comments during initial peer review of the draft manuscript.
The author is an employee of Exponent, Inc., a scientific consulting firm that
provides research and advice to private sector and government clients. The
author has been an expert witness retained by private clients in asbestos
litigation. The author declares no competing interests.
Availability of data and materials
The SEER 9 cancer incidence data analyzed in this manuscript is publically
available but is subject to a signed data use agreement which forbids sharing
the underlying data files. The NCI webtool for Age-Period-Cohort analysis is also
a publically available program which other researchers may access and apply
to the SEER 9 data (within the SEER data use agreement guidelines) to further
analyze and/or validate the analyses presented here.
Consent for publication
Ethics approval and consent to participate
Access to the SEER 9 database was obtained after execution of the SEER data use
agreement at: https://seer.cancer.gov/dataagreements/seer.pdf. The data
analyses and use of the SEER 9 database in this manuscript is in accordance with the
data use agreement and does not require Institutional Review Board approval or
other ethics approval or consent of the study subjects.
This work was funded internally by Exponent, Inc. and no outside party
participated in the design, data analysis, interpretation, or writing of this manuscript.
Springer Nature remains neutral with regard to jurisdictional claims in published
maps and institutional affiliations.
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