Cancer Incidence Trends in Successive Social Generations in the US.

Importance: The incidence of some cancers in the US is increasing in younger age groups, but underlying trends in cancer patterns by birth year remain unclear. Objective: To estimate cancer incidence trends in successive social generations. Design, Setting, and Participants: In this cohort study, incident invasive cancers were ascertained from the Surveillance, Epidemiology, and End Results (SEER) program's 13-registry database (November 2020 submission, accessed August 14, 2023). Invasive cancers diagnosed at ages 35 to 84 years during 1992 to 2018 within 152 strata were defined by cancer site, sex, and race and ethnicity. Exposure: Invasive cancer. Main Outcome and Measures: Stratum-specific semiparametric age-period-cohort (SAGE) models were fitted and incidence per 100 000 person-years at the reference age of 60 years was calculated for single-year birth cohorts from 1908 through 1983 (fitted cohort patterns [FCPs]). The FCPs and FCP incidence rate ratios (IRRs) were compared by site for Generation X (born between 1965 and 1980) and Baby Boomers (born between 1946 and 1964). Results: A total of 3.8 million individuals with invasive cancer (51.0% male; 8.6% Asian or Pacific Islander, 9.5% Hispanic, 10.4% non-Hispanic Black, and 71.5% non-Hispanic White) were included in the analysis. In Generation X vs Baby Boomers, FCP IRRs among women increased significantly for thyroid (2.76; 95% CI, 2.41-3.15), kidney (1.99; 95% CI, 1.70-2.32), rectal (1.84; 95% CI, 1.52-2.22), corpus uterine (1.75; 95% CI, 1.40-2.18), colon (1.56; 95% CI, 1.27-1.92), and pancreatic (1.39; 95% CI, 1.07-1.80) cancers; non-Hodgkins lymphoma (1.40; 95% CI, 1.08-1.82); and leukemia (1.27; 95% CI, 1.03-1.58). Among men, IRRs increased for thyroid (2.16; 95% CI, 1.87-2.50), kidney (2.14; 95% CI, 1.86-2.46), rectal (1.80; 95% CI, 1.52-2.12), colon (1.60; 95% CI, 1.32-1.94), and prostate (1.25; 95% CI, 1.03-1.52) cancers and leukemia (1.34; 95% CI, 1.08-1.66). Lung (IRR, 0.60; 95% CI, 0.50-0.72) and cervical (IRR, 0.71; 95% CI, 0.57-0.89) cancer incidence decreased among women, and lung (IRR, 0.51; 95% CI, 0.43-0.60), liver (IRR, 0.76; 95% CI, 0.63-0.91), and gallbladder (IRR, 0.85; 95% CI, 0.72-1.00) cancer and non-Hodgkins lymphoma (IRR, 0.75; 95% CI, 0.61-0.93) incidence decreased among men. For all cancers combined, FCPs were higher in Generation X than for Baby Boomers because gaining cancers numerically overtook falling cancers in all groups except Asian or Pacific Islander men. Conclusions and Relevance: In this model-based cohort analysis of incident invasive cancer in the general population, decreases in lung and cervical cancers in Generation X may be offset by gains at other sites. Generation X may be experiencing larger per-capita increases in the incidence of leading cancers than any prior generation born in 1908 through 1964. On current trajectories, cancer incidence could remain high for decades.

Does Sex Matter? Temporal Analyses of Melanoma Trends among Men and Women Suggest Etiologic Heterogeneity.

The incidence and distribution of cutaneous melanoma differ between the sexes, but it is unclear whether these differences have been constant through time or across generations. We compared incidence trends by age, sex, and anatomic site by analyzing long-term melanoma data (1982-2018) in 3 populations residing at high-, moderate-, and low-ambient sun exposure: Queensland, Australia; United States White; and Scotland. We fit age-period-cohort models and compared trends in the male-to-female incidence rate ratio by site and sex. In men, melanoma incidence was always highest on the trunk; in women, incidence was historically highest on limbs, but there have been recent increases in truncal melanoma among females in all populations. The incidence rate ratio showed excess melanoma on the lower limb in females in most age groups in all populations. In contrast, there was a male excess of melanoma on the trunk (from about age 25 years) and head/neck (from about age 40 years), which increased with age. Birth cohort analyses identified turning points in incidence from high to low incidence among recent birth cohorts, which differed by population and site. Changing exposure to UVR is implicated, possibly superimposed upon innate differences between the sexes in site-specific susceptibility.

Projected Incidence of Hepatobiliary Cancers and Trends Based on Age, Race, and Gender in the United States.

BACKGROUND: Identifying the projected incidence of hepatobiliary cancers and recognizing patient cohorts at increased risk can help develop targeted interventions and resource allocation. The expected incidence of subtypes of hepatobiliary cancers in different age groups, races, and genders remains unknown. METHODS: Historical epidemiological data from the Surveillance, Epidemiology, and End Results (SEER) database was used to project future incidence of hepatobiliary malignancies in the United States and identify trends by age, race, and gender. Patients ≥18 years of age diagnosed with a hepatobiliary malignancy between 2001 and 2017 were included. US Census Bureau 2017 National Population projects provided the projected population from 2017 to 2029. Age-Period-Cohort forecasting model was used to estimate future births cohort-specific incidence. All analyses were completed using R Statistical Software. RESULTS: We included 110381 historical patients diagnosed with a hepatobiliary malignancy between 2001 and 2017 with the following subtypes: hepatocellular cancer (HCC) (68%), intrahepatic cholangiocarcinoma (iCCA) (11.5%), gallbladder cancer (GC) (8%), extrahepatic cholangiocarcinoma (eCCA) (7.6%), and ampullary cancer (AC) (4%). Our models predict the incidence of HCC to double (2001 to 2029) from 4.5 to 9.03 per 100,000, with the most significant increase anticipated in patients 70-79 years of age. In contrast, incidence is expected to continue to decline among the Asian population. Incidence of iCCA is projected to increase, especially in the white population, with rates in 2029 double those in 2001 (2.13 vs. 0.88 per 100,000, respectively; p < 0.001). The incidence of GC among the black population is expected to increase. The incidence of eCCA is expected to significantly increase, especially among the Hispanic population, while that of AC will remain stable. DISCUSSION: The overall incidence of hepatobiliary malignancies is expected to increase in the coming years, with certain groups at increased risk. These findings may help with resource allocation when considering screening, treatment, and research in the coming years.

Comparative age-period-cohort analysis.

BACKGROUND: Cancer surveillance researchers analyze incidence or mortality rates jointly indexed by age group and calendar period using age-period-cohort models. Many studies consider age- and period-specific rates in two or more strata defined by sex, race/ethnicity, etc. A comprehensive characterization of trends and patterns within each stratum can be obtained using age-period-cohort (APC) estimable functions (EF). However, currently available approaches for joint analysis and synthesis of EF are limited. METHODS: We develop a new method called Comparative Age-Period-Cohort Analysis to quantify similarities and differences of EF across strata. Comparative Analysis identifies whether the stratum-specific hazard rates are proportional by age, period, or cohort. RESULTS: Proportionality imposes natural constraints on the EF that can be exploited to gain efficiency and simplify the interpretation of the data. Comparative Analysis can also identify differences or diversity in proportional relationships between subsets of strata ("pattern heterogeneity"). We present three examples using cancer incidence from the United States Surveillance, Epidemiology, and End Results Program: non-malignant meningioma by sex; multiple myeloma among men stratified by race/ethnicity; and in situ melanoma by anatomic site among white women. CONCLUSIONS: For studies of cancer rates with from two through to around 10 strata, which covers many outstanding questions in cancer surveillance research, our new method provides a comprehensive, coherent, and reproducible approach for joint analysis and synthesis of age-period-cohort estimable functions.

Smoothing Lexis diagrams using kernel functions: A contemporary approach.

Lexis diagrams are rectangular arrays of event rates indexed by age and period. Analysis of Lexis diagrams is a cornerstone of cancer surveillance research. Typically, population-based descriptive studies analyze multiple Lexis diagrams defined by sex, tumor characteristics, race/ethnicity, geographic region, etc. Inevitably the amount of information per Lexis diminishes with increasing stratification. Several methods have been proposed to smooth observed Lexis diagrams up front to clarify salient patterns and improve summary estimates of averages, gradients, and trends. In this article, we develop a novel bivariate kernel-based smoother that incorporates two key innovations. First, for any given kernel, we calculate its singular values decomposition, and select an optimal truncation point-the number of leading singular vectors to retain-based on the bias-corrected Akaike information criterion. Second, we model-average over a panel of candidate kernels with diverse shapes and bandwidths. The truncated model averaging approach is fast, automatic, has excellent performance, and provides a variance-covariance matrix that takes model selection into account. We present an in-depth case study (invasive estrogen receptor-negative breast cancer incidence among non-Hispanic white women in the United States) and simulate operating characteristics for 20 representative cancers. The truncated model averaging approach consistently outperforms any fixed kernel. Our results support the routine use of the truncated model averaging approach in descriptive studies of cancer.

Global epidemiologic patterns of oropharyngeal cancer incidence trends.

BACKGROUND: The emergence of human papillomavirus (HPV)-positive oropharyngeal cancer and evolving tobacco use patterns have changed the landscape of head and neck cancer epidemiology internationally. We investigated updated trends in oropharyngeal cancer incidence worldwide. METHODS: We analyzed cancer incidence data between 1993 and 2012 from 42 countries using the Cancer Incidence in Five Continents database volumes V through XI. Trends in oropharyngeal cancer incidence were compared with oral cavity cancers and lung squamous cell carcinomas using log-linear regression and age period-cohort modeling. RESULTS: In total, 156 567 oropharyngeal cancer, 146 693 oral cavity cancer, and 621 947 lung squamous cell carcinoma patients were included. Oropharyngeal cancer incidence increased (P < .05) in 19 and 23 countries in men and women, respectively. In countries with increasing male oropharyngeal cancer incidence, all but 1 had statistically significant decreases in lung squamous cell carcinoma incidence, and all but 2 had decreasing or nonsignificant net drifts for oral cavity cancer. Increased oropharyngeal cancer incidence was observed both in middle-aged (40-59 years) and older (≥60 years) male cohorts, with strong nonlinear birth cohort effects. In 20 countries where oropharyngeal cancer incidence increased for women and age period-cohort analysis was possible, 13 had negative or nonsignificant lung squamous cell carcinoma net drifts, including 4 countries with higher oropharyngeal cancer net drifts vs both lung squamous cell carcinoma and oral cavity cancer (P < .05 for all comparisons). CONCLUSIONS: Increasing oropharyngeal cancer incidence is seen among an expanding array of countries worldwide. In men, increased oropharyngeal cancer is extending to older age groups, likely driven by human papillomavirus-related birth cohort effects. In women, more diverse patterns were observed, suggesting a complex interplay of risks factors varying by country, including several countries where female oropharyngeal cancer increases may be driven by HPV.

Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States.

PURPOSE: Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. PATIENTS AND METHODS: HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020. CONCLUSION: Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.

Cancer in Costello syndrome: a systematic review and meta-analysis.

BACKGROUND: Costello syndrome (CS) is a cancer-predisposition disorder caused by germline pathogenic variants in HRAS. We conducted a systematic review using case reports and case series to characterise cancer risk in CS. METHODS: We conducted a systematic review to identify CS cases to create a retrospective cohort. We tested genotype-phenotype correlations and calculated cumulative incidence and hazard rates (HR) for cancer and cancer-free death, standardised incidence rates (SIR) and survival after cancer. RESULTS: This study includes 234 publications reporting 621 patients from 35 countries. Over nine percent had cancer, including rhabdomyosarcoma, bladder, and neuroblastoma. The rate of cancer and death associated with p.Gly12Ser were lower when compared to all other variants (P < 0.05). Higher mortality for p.Gly12Cys, p.Gly12Asp, p.Gly12Val and p.Gly60Val and higher malignancy rate for p.Gly12Ala were confirmed (P < 0.05). Cumulative incidence by age 20 was 13% (cancer) and 11% (cancer-free death). HR (death) was 3-4% until age 3. Statistically significant SIRs were found for rhabdomyosarcoma (SIR = 1240), bladder (SIR = 1971), and neuroblastoma (SIR = 60). Survival after cancer appeared reduced. CONCLUSIONS: This is the largest investigation of cancer in CS to date. The high incidence and SIR values found to highlight the need for rigorous surveillance and evidence-based guidelines for this high-risk population.

Advances in statistical methods for cancer surveillance research: an age-period-cohort perspective.

Background: Analysis of Lexis diagrams (population-based cancer incidence and mortality rates indexed by age group and calendar period) requires specialized statistical methods. However, existing methods have limitations that can now be overcome using new approaches. Methods: We assembled a "toolbox" of novel methods to identify trends and patterns by age group, calendar period, and birth cohort. We evaluated operating characteristics across 152 cancer incidence Lexis diagrams compiled from United States (US) Surveillance, Epidemiology and End Results Program data for 21 leading cancers in men and women in four race and ethnicity groups (the "cancer incidence panel"). Results: Nonparametric singular values adaptive kernel filtration (SIFT) decreased the estimated root mean squared error by 90% across the cancer incidence panel. A novel method for semi-parametric age-period-cohort analysis (SAGE) provided optimally smoothed estimates of age-period-cohort (APC) estimable functions and stabilized estimates of lack-of-fit (LOF). SAGE identified statistically significant birth cohort effects across the entire cancer panel; LOF had little impact. As illustrated for colon cancer, newly developed methods for comparative age-period-cohort analysis can elucidate cancer heterogeneity that would otherwise be difficult or impossible to discern using standard methods. Conclusions: Cancer surveillance researchers can now identify fine-scale temporal signals with unprecedented accuracy and elucidate cancer heterogeneity with unprecedented specificity. Birth cohort effects are ubiquitous modulators of cancer incidence in the US. The novel methods described here can advance cancer surveillance research.

Alternative stopping rules to limit tree expansion for random forest models.

Random forests are a popular type of machine learning model, which are relatively robust to overfitting, unlike some other machine learning models, and adequately capture non-linear relationships between an outcome of interest and multiple independent variables. There are relatively few adjustable hyperparameters in the standard random forest models, among them the minimum size of the terminal nodes on each tree. The usual stopping rule, as proposed by Breiman, stops tree expansion by limiting the size of the parent nodes, so that a node cannot be split if it has less than a specified number of observations. Recently an alternative stopping criterion has been proposed, stopping tree expansion so that all terminal nodes have at least a minimum number of observations. The present paper proposes three generalisations of this idea, limiting the growth in regression random forests, based on the variance, range, or inter-centile range. The new approaches are applied to diabetes data obtained from the National Health and Nutrition Examination Survey and four other datasets (Tasmanian Abalone data, Boston Housing crime rate data, Los Angeles ozone concentration data, MIT servo data). Empirical analysis presented herein demonstrate that the new stopping rules yield competitive mean square prediction error to standard random forest models. In general, use of the intercentile range statistic to control tree expansion yields much less variation in mean square prediction error, and mean square prediction error is also closer to the optimal. The Fortran code developed is provided in the Supplementary Material.

Incidence of in Situ vs Invasive Melanoma: Testing the "Obligate Precursor" Hypothesis.

BACKGROUND: Melanoma incidence has been rising in populations with predominantly European ancestry (White), speculated to be partly driven by heightened detection of indolent tumors. If in situ melanomas are destined to evolve to invasive cancers, detecting and removing them should deplete the pool of invasive lesions, and people with in situ melanoma should, on average, be younger than those with invasive melanoma. METHODS: We analyzed long-term incidence trends (1982-2018) for in situ and invasive melanomas in 3 predominantly White populations with high, medium, and low melanoma rates: Queensland (Australia), United States White, and Scotland. We calculated the incidence rate ratio (IRR) of in situ to invasive melanomas and estimated the contributions of age, period, and cohort effects. We compared age at diagnosis of in situ vs invasive melanomas overall and stratified by sex and anatomic site. RESULTS: In all 3 populations, the in situ to invasive incidence rate ratio increased statistically significantly from less than 0.3 in 1982 to 1.95 (95% confidence interval [CI] = 1.88 to 2.02) in Queensland, 0.93 (95% CI = 0.90 to 0.96) in the US White population, and 0.58 (95% CI = 0.54 to 0.63) in Scotland in 2018. The mean age at diagnosis of in situ melanomas was the same or higher than invasive melanomas for almost all time periods among men and women and on all body sites except the lower limbs. CONCLUSIONS: The increasing ratio of in situ to invasive melanoma incidence over time, together with the high (and increasing) mean age at diagnosis of in situ melanomas, is consistent with more indolent lesions coming to clinical attention than in previous eras.

Reverse engineering the FRAX algorithm: Clinical insights and systematic analysis of fracture risk.

The Fracture Risk Assessment Tool (FRAX) is a computational tool developed to predict the 10-year probability of hip fracture and major osteoporotic fracture based on inputs of patient characteristics, bone mineral density (BMD), and a set of seven clinical risk factors. While the FRAX tool is widely available and clinically validated, its underlying algorithm is not public. The relative contribution and necessity of each input parameter to the final FRAX score is unknown. We systematically collected hip fracture risk scores from the online FRAX calculator for osteopenic Caucasian women across 473,088 unique inputs. This dataset was used to dissect the FRAX algorithm and construct a reverse-engineered fracture risk model to assess the relative contribution of each input variable. Within the reverse-engineered model, age and T-Score were the strongest contributors to hip fracture risk, while BMI had marginal contribution. Of the clinical risk factors, parent history of fracture and ongoing glucocorticoid treatment had the largest additive effect on risk score. A generalized linear model largely recapitulated the FRAX tool with an R2 of 0.91. Observed effect sizes were then compared to a true patient population by creating a logistic regression model of the Study of Osteoporotic Fractures (SOF) cohort, which closely paralleled the effect sizes seen in the reverse-engineered fracture risk model. Analysis identified several clinically relevant observations of interest to FRAX users. The role of major osteoporotic fracture risk prediction in contributing to an indication of treatment need is very narrow, as the hip fracture risk prediction accounted for 98% of treatment indications for the SOF cohort. Removing any risk factor from the model substantially decreased its accuracy and confirmed that more parsimonious models are not ideal for fracture prediction. For women 65 years and older with a previous fracture, 98% of FRAX combinations exceeded the treatment threshold, regardless of T-score or other factors. For women age 70+ with a parent history of fracture, 99% of FRAX combinations exceed the treatment threshold. Based on these analyses, we re-affirm the efficacy of the FRAX as the best tool for fracture risk assessment and provide deep insight into the interplay between risk factors.

Decreasing Incidence of Estrogen Receptor-Negative Breast Cancer in the United States: Trends by Race and Region.

BACKGROUND: Incidence of estrogen receptor (ER)-negative breast cancer, an aggressive subtype, is highest in US African American women and in Southern residents but has decreased overall since 1992. We assessed whether ER-negative breast cancer is decreasing in all age groups and cancer registries among non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic White (HW) women. METHODS: We analyzed 17 Surveillance, Epidemiology, and End-Results (SEER) Program registries (12 for 1992-2016; 5 for 2000-2016) to assess NHW, NHB, and HW trends by ER status and age group (30-39 years, 40-49 years, 50-69 years, 70-84 years). We used hierarchical age-period-cohort models that account for sparse data, which improve estimates to quantify between-registry heterogeneity in mean incidence rates and age-adjusted trends vs SEER overall. RESULTS: Overall, ER-negative incidence was highest in NHB, then NHW and HW women, and decreased from 1992-2016 in each age group and racial or ethnic group. The greatest decrease was for HW women aged 40-49 years, with an annual percent change of -3.5%/y (95% credible interval = -4.4%, -2.7%) averaged over registries. The trend heterogeneity was statistically significant in every race or ethnic and age group. Furthermore, the incidence relative risks by race or ethnicity compared with the race-specific SEER average were also statistically significantly heterogeneous across the majority of registries and age groups (62 of 68 strata). The greatest heterogeneity was seen in HW women, followed by NHB women, and the least in NHW women. CONCLUSIONS: Decreasing ER-negative breast cancer incidence differs meaningfully by US region and age among NHB and HW women. Analytical studies including minority women from higher and lower incidence areas may provide insights into breast cancer racial disparities.

Geographic disparities of breast cancer incidence in Portugal at the district level: A spatial age-period-cohort analysis, 1998-2011.

BACKGROUND: Breast cancer is the most common malignancy in women world-wide and the most common cause of cancer deaths, which can often be managed with early diagnosis and subsequent treatment. Here, we focus on geographic disparities in incidence within Portugal for three age groups of women (30-49; 50-69; 70-84 years). METHODS: Age-period-cohort (APC) models are widely used in cancer surveillance, and these models have recently been extended to allow spatially-varying effects. We apply novel spatial APC models to estimate relative risk and age-adjusted temporal trends at the district level for the 20 districts in Portugal. Our model allows us to report on country-wide trends, but also to investigate geographic disparities between districts and trends within districts. RESULTS: Age-adjusted breast cancer incidence was increasing over 1998-2011 for all three age groups and in every district in Portugal. However, we detect spatially-structured between-district heterogeneity in relative risk and age-adjusted trends (Net Drifts) for each of the three age groups, which is most pronounced in the highly-screened (50-69yo) and late-onset (70-84yo) groups of women. CONCLUSIONS: We present evidence of disparities in breast cancer incidence at a more granular geographic level than previously reported. Some disparities may be due to latent risk factors, which cannot be accounted for by age, birth year, and geographic location alone. IMPACT: Our study motivates resuming data collection for breast cancer incidence at the district level in Portugal, as well as the study of exogenous risk factors.

Incidence of Benign Meningiomas in the United States: Current and Future Trends.

Background: Benign meningiomas are the most frequently reported central nervous system tumors in the United States, with increasing incidence in past decades. However, the future trajectory of this neoplasm remains unclear. Methods: We analyzed benign meningioma incidence of cases identified by any means (eg, radiographically with or without microscopic confirmation) in US Surveillance, Epidemiology, and End Results cancer registries among groups aged 35 to 84 years during 2004-2017 by sex and race and ethnicity using age-period-cohort models. We employed age-period-cohort forecasting models to glean insights regarding the etiology, distribution, and anticipated future (2018-2027) public health impact of this neoplasm. Results: In all groups, meningioma incidence overall increased through 2010, then stabilized. Temporal declines were statistically significant overall and in most groups. JoinPoint analysis of cohort rate-ratios identified substantial acceleration in White men born after 1963 (from 1.1% to 3.2% per birth year); cohort rate-ratios were stable or increasing in all groups and all birth cohorts. We forecast that meningioma incidence through 2027 will remain stable or decrease among groups aged 55-84 years but remain similar to current levels among groups aged 35-54 years. The case count of total meningioma burden in 2027 is expected to be approximately 30 470, similar to the expected case count of 27 830 in 2018. Conclusions: Between 2004 and 2017, overall incidence of benign meningioma increased and then stabilized or declined. For 2018-2027, our forecast is incidence will remain generally stable in younger age groups but decrease in older age groups. Nonetheless, the total future burden will remain similar to current levels because the population is aging.

A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype.

Importance: Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort. Objective: To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment. Design, Setting, and Participants: This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018. Main Outcomes and Measures: Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry. Results: A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype. Conclusions and Relevance: This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.

Incidence of Hip Fracture Over 4 Decades in the Framingham Heart Study.

Importance: Age-adjusted hip fracture incidence is decreasing in the US. The decrease has been attributed to osteoporosis treatment, but the cause is unknown. Objective: To examine the decrease in hip fracture incidence over the past 40 years in the US. Design, Setting, and Participants: A population-based cohort study using participants in the Framingham Heart Study was conducted. A total of 4918 men and 5634 women were followed up prospectively for the first hip fracture between January 1, 1970, and December 31, 2010. Data were analyzed from May 1, 2019, to May 30, 2020. Main Outcomes and Measures: Incidence of hip fracture and contemporaneous prevalence of risk factors for hip fractures analyzed with age-period-cohort models. Results: The study contained more than 105 000 person-years in 10 552 individuals with a gradual shift toward the offspring participants in the 1980s and 1990s. Women represented more than 55% of the study sample over the years. Adjusted for age, the incidence of hip fracture decreased by 4.4% (95% CI, 6.8%-1.9%) per year from 1970 to 2010. Both period associations (P < .001) and birth cohort associations (P < .001) were statistically significant. For example, in persons aged 85 to 89 years, the incidence of hip fracture was 759 per 100 000 person-years in the offspring group compared with 2018 per 100 000 person-years in the original cohort. The decrease in hip fracture incidence was coincident with a decrease in smoking and heavy drinking. Smoking decreased from 38% in the 1970s to 15% in the late 2000s, while heavy drinking decreased from 7.0% to 4.5%. The prevalence of other risk factors for hip fracture, such as underweight (body mass index <18.5), obesity (body mass index >30), and early menopause (age <45 years) were stable over the study period. When persons who never smoked were evaluated, a change in the incidence of -3.2% (95% CI, -6.0% to -0.4%) per year was observed. The difference between the decrease of the entire population and nonsmokers of 1.5% per year was similar to the hazard ratio conferred by smoking (hazard ratio, 1.5; 95% CI, 1.14-1.96). Conclusions and Relevance: In this study, individuals born more recently appeared to have a low risk for hip fracture. Reductions in smoking and heavy drinking were the risk factor changes coincident with the observed decrease in hip fracture. Attributing the decrease in hip fracture incidence up to 2010 solely to better treatment is not supported by these data, emphasizing the need to treat patients with osteoporosis while continuing to encourage public health interventions for smoking cessation and heavy drinking.