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We investigate whether number of episodes (NoEs) meaningfully reflect genetic risk and genetic heterogeneity for five primary disorders-Drug Use Disorder (DUD), Alcohol Use Disorder (AUD), Major Depression (MD), Bipolar Disorder (BD), and Schizophrenia (SZ) ascertained from Swedish population registries. We utilize Genetic Risk Ratios (GRR)-defined as the ratio of the genetic risk for secondary disorders to the genetic risk for the primary disorder-derived from Family Genetic Risk Scores (FGRS). For all five primary disorders, genetic risk rose robustly with increasing NoEs. For both AUD and DUD, the GRR for all six secondary disorders-selected to have a likely genetic relationship with the particular primary disorder-declined with increasing NoEs so that cases of AUD and DUD with high versus low NoEs had both a higher genetic risk and a purer genetic signal. With MD, genetic risk maximized at an intermediate NoEs. While the GRRs for AUD and DUD in MD cases dropped sharply with increasing NoEs, GRR for BD increased. For BD, genetic risk rose sharply with increasing NoEs while for all secondary disorders the GRRs showed a mixture of modest increases and decreases. Like AUD and DUD, but even more markedly, selecting BD cases with high rates of recurrence would produce a sample with a high overall genetic risk and a relatively homogeneous genetic signal. For SZ, genetic risk rose moderately with increases in NoEs. GRRs for other non-affective psychoses (ONAP) and autism spectrum disorder (ASD) fell quite slowly with increasing NoEs, and more rapidly for other secondary disorders. Cases of SZ with high recurrence rates had a high genetic risk and a relatively pure signal, albeit with contributions from ONAP and ASD. In summary, NOEs are a robust index of genetic risk and genetic heterogeneity across our primary disorders with important inter-disorder differences.

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BACKGROUND: Men with prostate cancer (PC) may experience significant psychosocial distress from physical symptoms, treatment side effects, or fear of recurrence. However, little is known about the long-term risk of anxiety disorders in men with PC. METHODS: A national cohort study was conducted of 180,189 men diagnosed with PC during 1998-2017 and 1,801,890 age-matched population-based control men in Sweden. Anxiety disorders were ascertained from nationwide outpatient and inpatient records through 2018. Cox regression was used to estimate hazard ratios (HRs) while adjusting for sociodemographic factors and prior psychiatric disorders. Subanalyses explored differences by PC treatment during 2005-2017. RESULTS: In 7.8 million person-years of follow-up, 94,387 (5%) men were diagnosed with anxiety disorders. Men with high-risk PC had a nearly 2-fold higher risk of anxiety disorders than control men without PC (adjusted HR, 1.96; 95% CI, 1.87-2.05). This risk was highest in the first 3 months after PC diagnosis (adjusted HR, 2.99; 95% CI, 2.49-3.59) but remained significantly elevated ≥10 years later (adjusted HR, 1.53; 95% CI, 1.35-1.74). Those treated only with androgen deprivation therapy (ADT) had the highest risk of anxiety disorders (adjusted HR, 2.08; 95% CI, 1.93-2.25). Men with low- or intermediate-risk PC had a modestly increased risk (adjusted HR, 1.39; 95% CI, 1.34-1.44). CONCLUSIONS: In this large national cohort, men with PC had substantially increased risk of anxiety disorders, especially those with high-risk PC and treated only with ADT. Men with PC need close monitoring for timely detection and treatment of anxiety symptoms, particularly shortly after PC diagnosis.

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Purpose: We aimed to analyze the risk of hereditary hemochromatosis (HH) among first-generation and second-generation immigrants in Sweden using Swedish-born individuals and Swedish-born individuals with Swedish-born parents as referents, respectively. Methods: All individuals aged 18 years of age and older, n = 6,180,500 in the first-generation study, and n = 4,589,930 in the second-generation study were included in the analyses. HH was defined as at least one registered diagnosis International Classification of Diseases 10th edition (E83.1) in the National Patient Register between January 1, 1998 and December 31, 2018. Cox regression was used to estimate the hazard ratios (HRs) with 99% confidence intervals (CI) owing to multiple testing, of incident HH with adjustments for age, cancer, other comorbidities, and socio-demographics. Results: In the first-generation study, there were 5,112 cases of HH, and in the second-generation study 4,626 cases of HH. The adjusted HRs for first-generation men and women overall were 0.72 (99% CI: 0.63-0.82) and 0.61 (99% CI: 0.52-0.72), respectively, and for the second-generation men and women 0.72 (99% CI: 0.62-0.83) and 0.97 (99% CI: 0.83-1.14), respectively, with a higher risk found only among first-generation men from Western Europe, HR 1.47 (99% CI: 1.05-2.06), compared to the control group. Conclusions: Our findings indicate that the overall risk of HH was lower among both first-generation and second-generation immigrants when compared to individuals born in Sweden or with Swedish-born parents. An elevated risk for HH was observed exclusively among first-generation men originating from Western Europe. These findings represent new knowledge and should be of global interest.

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OBJECTIVE: There is growing interest in how peers' genotypes may influence health (i.e., peer social genetic effects). The authors sought to clarify the nature of peer social genetic effects on risk for drug use disorder, alcohol use disorder (AUD), major depression, and anxiety disorder. METHOD: Cox models were used with data from a population-based Swedish cohort (N=655,327). Outcomes were drug use disorder, AUD, major depression, and anxiety disorder registrations between ages 17 and 30 from medical, criminal, and pharmacy registries. The authors indexed peer social genetic effects with peers' family genetic risk scores (FGRSs) for the same disorders, which are personalized measures of genetic risk inferred from diagnoses in first- to fifth-degree relatives. RESULTS: Across disorders, peer FGRSs predicted increased risks of proband registration (hazard ratio range, 1.01-1.59), with stronger effects for drug use disorder and AUD than for major depression and anxiety disorder. Peer social genetic effects were stronger for school classmates than for geographically proximal peers, and for peers from upper secondary school (ages 16-19) versus peers from lower secondary school (ages 7-16). Peer social genetic effects remained significant following statistical control for sociodemographic confounders, whether peers were affected, and peers' FGRS for educational attainment. Peer social genetic effects were more pronounced for probands at higher genetic risk. CONCLUSIONS: The genetic makeup of adolescents' peers has long-reaching consequences on risks for drug use disorder, AUD, major depression, and anxiety disorder. Individuals at high genetic risk are more sensitive to social genetic effects. Alternative hypotheses such as sociodemographic stratification, exposure to affected peers, and genetic predispositions for educational attainment did not explain the risk associated with peer social genetic effects for substance use and psychiatric disorders.

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BACKGROUND: There is increasing evidence implicating hemoglobin/heme and their scavengers in oxidative stress-mediated pathologies, but information is limited in abdominal aortic aneurysm (AAA). METHODS AND RESULTS: In this case-control study, we assessed heme/heme-related markers in 142 men with AAA and 279 men with a normal aortic diameter consecutively recruited from an ultrasound screening program in Sweden. Enzyme-linked immunosorbent assays (ELISAs) were used to measure heme oxygenase-1 (HO-1) and hemopexin (Hpx) plasma levels, colorimetric assays for cell-free heme and whole blood hemoglobin (Hb) levels, and droplet digital PCR (ddPCR) and real-time PCR to determine haptoglobin (Hp) (pheno)type and genotype, respectively. Hpx and heme plasma levels at baseline were elevated, while HO-1 levels were lower in men with AAA (p < 0.001) and were significantly associated with AAA prevalence independently of potential confounders. A combination of heme and HO-1 showed the best diagnostic potential based on the area under the curve (AUC): 0.76, sensitivity: 80%, specificity: 48%. Additionally, when previously described inflammatory biomarker interleukin-6 (IL-6), was added to our model it significantly improved the diagnostic value (AUC: 0.87, sensitivity: 80%, specificity: 79%) compared to IL-6 alone (AUC: 0.73, sensitivity: 80%, specificity: 49%). Finally, Hb (positively) and Hpx (negatively) levels at baseline were associated with AAA growth rate (mm/year), and their combination showed the best prognostic value for discriminating fast and slow-growing AAA (AUC: 0.76, sensitivity: 80%, specificity: 62%). CONCLUSIONS: This study reports the distinct disruption of heme and related markers in both the development and progression of AAA, underscoring their potential in aiding risk stratification and therapeutic strategies.

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Background: Mitochondrial DNA copy number (mtDNA-CN) is associated with aging. A relationship between mtDNA-CN and degenerative disorders, e.g. osteoarthritis (OA) and osteoporosis (OP), has been suggested. We aimed to investigate the relationship of mtDNA-CN and incident OA and OP. Materials and methods: MtDNA-CN was studied in relationship to incident OA and OP in a population-based cohort study of 6916 middle-aged women (52-63 years). Totally 2521 women with sufficient quality of mtDNA were analyzed. After exclusions, 1978 women remained in the study population. Four different endpoints obtained from the National Patient register were studied: 1) OA, 2) OP 3) OA surgery, and 4) OP fracture. In the multivariate model adjustments were made for potential OA and OP risk factors. Results: Women with low mtDNA-CN were older and had more activity at work. 125 women (6.32%) were affected by incident OP and 254 women (12.84%) had an OP fracture. Incident OA affected 451 women (22.80%) and 175 women (8.85%) had OA surgery. There were no associations between mtDNA-CN and incident risk of OA (Hazard ratio â€‹= â€‹1.00, 95% confidence interval 0.83-1.20), OA surgery (0.79, 0.58-1.07), OP (0.89, 0.62-1.27), or OP fracture (1.00, 0.78-1.29). However, incident OP was significantly associated with T-score (bone density), smoking, diabetes mellitus, and chronic obstructive bronchitis (COPD). OA was associated with body mass index and COPD. Conclusions: The present study suggests that mtDNA-CN, reflecting mitochondrial dysfunction, is not a major predictor for incident OA or OP. However, due to the limited study size minor associations cannot be excluded.

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Using a case-controlled study including siblings of major depression (MD) and control probands, born 1970-1990 and followed through 2018, we sought to clarify the degree to which the familial liability to MD is reflected in its clinical features, and the pattern of psychiatric disorders at elevated risk in the siblings of MD probands. The study population included full-siblings of 197,309 MD and matched 197,309 control probands. The proband-sibling tetrachoric correlation of for MD was +0.20. Both linear and quadratic effects of younger AAO and number of episodes significantly increased the risk of MD in siblings. Male sex, anxiety disorder, alcohol use disorder (AUD), inpatient treatment, psychotic symptoms, severity, and antidepressant prescription in MD probands increased the risk of MD in siblings. Cox proportional hazard models (hazard ratios, 95% CI) revealed a significantly increased risk of attention deficit hyperactivity disorder (1.82, 1.76-1.88), generalized anxiety disorder (1.79, 1.74-1.85), bipolar disorder (1.78, 1.70-1.85), MD (1.74, 1.72-1.76), obsessive-compulsive disorder (1.72, 1.65-1.80), phobic anxiety disorder (1.71, 1.65-1.76), and panic disorder (1.68, 1.64-1.72) in MD co-siblings. The HRs for AUD (1.64, 1.60-1.68), post-traumatic stress disorder (1.62, 1.59-1.66) were modestly lower, and the lowest was seen for schizophrenia (1.42, 1.30-1.54). The overall pattern of increased risk of these disorders was similar in reared-apart half-siblings and cousins of MD probands. Our findings suggest that MD is familial, and a range of important clinical factors predict its familial liability. The familial liability to MD, mostly due to genetic factors, is shared with a broad range of psychiatric disorders.

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PURPOSE: We aimed at analysing the risk of congestive heart failure (CHF) among first- and second-generation immigrants in younger age groups. METHODS: All individuals aged 18-54 years, n = 3 973 454 in the first-generation study and n = 3 817 560 in the second-generation study, were included. CHF was defined as at least one registered diagnosis in the National Patient Register between 1 January 1998 and 31 December 2018. Cox regression analysis was used to estimate the relative risk [hazard ratios (HRs) with 99% confidence intervals (CIs)] of incident CHF with adjustments for age, co-morbidities and socio-demographics. RESULTS: In the first-generation study, a total of 85 719 cases of CHF were registered, 54 369 men and 31 350 women, where fully adjusted models showed HRs for all foreign-born men of 1.12 (99% CI 1.06-1.17) and for women of 0.99 (0.92-1.05). Groups with higher risk included men from Eastern Europe, Central Europe, Africa and Asia and women from Africa and Asia, and a lower risk was found among Latin American women. In the second-generation study, a total of 88 999 cases of CHF were registered, 58 403 men and 30 596 women, where fully adjusted models showed HRs for second-generation men of 1.04 (0.99-1.09) and women of 0.97 (0.90-1.04). CONCLUSIONS: The higher risk in some foreign-born groups needs to be paid attention to in clinical practice. The fact that almost all increased risks were attenuated and absent in second-generation immigrants suggests that lifestyle and environmental factors are more important than genetic differences in the risk of CHF.

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The human sex ratio at birth (SRB) undergoes temporary changes around a mean proportion of 0.51 male births. SRB has been well studied for historical, geographical, and secular trends, but until now not linked to health outcomes in the total population, e.g. for cardiovascular disease (CVD) or mortality during follow-up of birth cohorts. We used linkage analysis based on national registers in Sweden that cover all births from 1900 to 2016. SRB at birth was calculated by every 10-year birth cohort in all survivors living in 1997 for a follow-up analysis of risk of CVD and mortality with data from national registers. When the highest quartile of SRB was used as reference, a slightly increased risk of fatal CVD (HR 1.03 (95% confidence intervals, CI): 1.02-1.04), non-fatal CVD (HR 1.01; 95%CI: 1.01-1.02) and mortality (HR 1.02; 95%CI, 1.01-1.03) was found after full adjustments in men belonging to the lowest SRB quartile. A similar pattern was also found for fatal CHD in women. in the lowest SBR quartile compared to the highest, HR 1.03 (95%CI: 1.02-1.05). In conclusion, in birth cohorts with a relatively lower than expected number of males born, long-term adverse health effects were observed with slightly increased cardiovascular risk and total mortality at the population level. This could indicate that men belonging to so-called "culled cohorts" in a developed country during the 20th century are characterized by a slightly increased risk that could reflect negative early life influences and environmental exposures in pregnant women resulting in selective loss of male embryos or fetuses. In a public health perspective SRB could be of some importance to monitor as an aspect of birth statistics linked to relatively minor population health effects.

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BACKGROUND AND HYPOTHESIS: To clarify, in a large, representative, longitudinal sample, the rate and predictors of diagnostic conversion from Bipolar Disorder (BD) to Schizophrenia (SZ) and from SZ→BD. DESIGN: From individuals born in Sweden 1950-1995 and living there in 1970 or later, we identified at least one initial diagnoses of SZ (n = 8449) and BD (n = 8438) followed for a minimum of 10 and a mean of 24 years. Diagnostic conversion required, respectively, at least two final diagnoses of BD and SZ 30 days apart with no intervening diagnosis of SZ or BD. RESULTS: At follow-up, rates of BD→SZ and SZ→BD conversion were 10.1 and 4.5%, respectively. Conversions occurred slowly, with around 50% completed in the first decade. Using a diverse range of variables available at first onset including family genetic risk scores, BD→SZ conversion was predicted with greater accuracy (AUC = 0.78) than SZ→BD conversion (AUC = 0.65). The strongest predictors of BD→SZ conversion were earlier years of birth, younger age at BD onset, low BD genetic risk, and being unmarried at BD onset. SZ→BD conversion was most strongly predicted by high BD genetic risk, being married at SZ onset, female sex, early age at SZ onset, and an MD episode prior to SZ onset. Cases of BD and SZ in the highest decile for conversion risk had HRs for a diagnostic change of, respectively, 12.5 and 3.4. CONCLUSIONS: Diagnostic conversion of BD→SZ and SZ→BD are not rare, are moderately predictable, and should likely be accounted for in many research designs.

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Importance: Twin studies have found that posttraumatic stress disorder (PTSD) is influenced by both genetic and environmental factors within a generation. No study has used an adoption design, which can address questions about the degree and sources of cross-generational transmission of adverse stress responses (ASRs) and PTSD. Objectives: To examine whether ASRs or PTSD are transmitted from parents to offspring, and to clarify the relative importance of genes and rearing. Design, Setting, and Participants: This cohort study used nationwide Swedish registry data from parents and offspring (n = 2 194 171, born 1960-1992) of 6 types of families (intact; had not lived with biological father; had not lived with biological mother; lived with stepfather; lived with stepmother; and adoptive). Follow-up occurred on December 31, 2018, and data were analyzed from March 3, 2023, to January 16, 2024. Exposures: Three sources of parent-offspring resemblance: genes plus rearing, genes only, and rearing only. Main Outcomes and Measures: Diagnoses of ASRs or PTSD were obtained from national inpatient, outpatient, and primary care medical registries. Parent-child resemblance was assessed by tetrachoric correlation. Sensitivity analyses were conducted to control for possible shared traumatic events. Results: The study population included 2 194 171 individuals of 6 family types (1 146 703 [52.3%] male; median [range] age, 42 [20-63] years). The weighted tetrachoric correlations across family types were 0.15 (95% CI, 0.15-0.16) for genes plus rearing, 0.08 (95% CI, 0.06-0.11) for genes only, and 0.10 (95% CI, 0.07-0.12) for rearing only. Controlling for potential shared traumatic events, sensitivity analyses found that the correlation for rearing decreased, with the most conservative control (exclusion of parent-offspring dyads with onset of ASRs or PTSD within 1 year) suggesting equal correlations with genes and rearing. Conclusions and Relevance: Diagnosis of ASRs or PTSD demonstrated cross-generational transmission, including both genetic and rearing correlations. Sensitivity analyses suggested that shared traumatic events partially accounted for the observed rearing correlations.

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OBJECTIVE: Twin studies have demonstrated that posttraumatic stress disorder (PTSD) is moderately heritable, and the pattern of findings across studies suggests higher heritability in females compared with males. Formal testing of sex differences has yet to be done in twin studies of PTSD. The authors sought to estimate the genetic and environmental contributions to PTSD, and to formally test for sex differences, in the largest sample to date of both sexes, among twins and siblings. METHODS: Using the Swedish National Registries, the authors performed structural equation modeling to decompose genetic and environmental variance for PTSD and to formally test for quantitative and qualitative sex differences in twins (16,242 pairs) and in full siblings within 2 years of age of each other (376,093 pairs), using diagnostic codes from medical registries. RESULTS: The best-fit model suggested that additive genetic and unique environmental effects contributed to PTSD. Evidence for a quantitative sex effect was found, such that heritability was significantly greater in females (35.4%) than males (28.6%). Evidence of a qualitative sex effect was found, such that the genetic correlation was high but less than complete (rg=0.81, 95% CI=0.73-0.89). No evidence of shared environment or special twin environment was found. CONCLUSIONS: This is the first demonstration of quantitative and qualitative sex effects for PTSD. The results suggest that unique environmental effects, but not the shared environment, contributed to PTSD and that genetic influences for the disorder are stronger in females compared with males. Although the heritability is highly correlated, it is not at unity between the sexes.

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To examine whether the level of genetic risk in psychiatric disorders impacts the social functioning of affected individuals, we examine the relationship between genetic risk factors for major depression (MD), anxiety disorders (AD), bipolar disorder (BD), non-affective psychosis (NAP), alcohol use disorder (AUD), and drug use disorder (DUD) in disordered individuals and five adverse social outcomes: unemployment, residence in areas of social deprivation, social welfare, early retirement, and divorce. We examine all cases with registration for these disorders from 1995 to 2015 in individuals born in Sweden. Genetic risk was assessed by the family genetic risk score (FGRS) and statistical estimates by Cox proportional hazard models. High genetic risk was significantly and modestly associated with poorer social outcomes in 23 of 30 analyses. Overall, genetic risk for MD, AD, AUD, and DUD impacted social functioning more strongly in affected individuals than did genetic risk for BD and NAP. Social welfare had the strongest associations with genetic risk, and residence in areas of high deprivation had the weakest. In individuals suffering from psychiatric and substance use disorders, high levels of genetic risk impact not only clinical features but also diverse measures of social functioning.

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OBJECTIVE: To examine long-term diabetes risk after preterm delivery or hypertensive disorders of pregnancy in a large population-based cohort. METHODS: This retrospective cohort study included all women with a singleton delivery in Sweden during 1973-2015 and no preexisting diabetes mellitus. Participants were followed up for development of type 2 diabetes identified from nationwide outpatient and inpatient diagnoses through 2018. Cox regression was used to compute hazard ratios (HRs) for the association between preterm delivery or hypertensive disorders of pregnancy and type 2 diabetes with adjustment for gestational diabetes and other maternal factors. Co-sibling analyses assessed for confounding by shared familial (genetic or environmental) factors. RESULTS: Overall, 2,184,417 women were included. Within 10 years after delivery, adjusted HRs for type 2 diabetes associated with specific pregnancy outcomes were as follows: any preterm delivery (before 37 weeks of gestation), 1.96 (95% CI, 1.83-2.09); extremely preterm delivery (22-27 weeks), 2.53 (95% CI, 2.03-3.16); and hypertensive disorders of pregnancy, 1.52 (95% CI, 1.43-1.63). All HRs remained significantly elevated (1.1-1.7-fold) 30-46 years after delivery. These findings were largely unexplained by shared familial factors. CONCLUSION: In this large national cohort, preterm delivery and hypertensive disorders of pregnancy were associated with increased risk for type 2 diabetes up to 46 years later. Women with these pregnancy complications are candidates for early preventive actions and long-term monitoring for type 2 diabetes.

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ABSTRACT: Hereditary angioedema (HAE), caused by C1 inhibitor protein deficiency, was recently shown to be associated with an increased risk for venous thromboembolism (VTE). To our knowledge, this is the first national family study of HAE, which aimed to determine the familial risk of VTE. The Swedish Multi-Generation Register was linked to the Swedish National Patient Register for the period of 1964 to 2018. Only patients with HAE with a validated diagnosis were included in the study and were linked to their family members. Hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE were calculated for patients with HAE in comparison with relatives without HAE. Among 2006 individuals (from 276 pedigrees of 365 patients with HAE), 103 individuals were affected by VTE. In total, 35 (9.6%) patients with HAE were affected by VTE, whereas 68 (4.1%) non-HAE relatives were affected (P < .001). The adjusted HR for VTE among patients with HAE was 2.51 (95% CI, 1.67-3.77). Patients with HAE were younger at the first VTE than their non-HAE relatives (mean age, 51 years vs 63 years; P < .001). Before the age of 70 years, the HR for VTE among patients with HAE was 3.62 (95% CI, 2.26-5.80). The HR for VTE for patients with HAE born after 1964 was 8.29 (95% CI, 2.90-23.71). The HR for VTE for patients with HAE who were born in 1964 or earlier was 1.82 (95% CI, 1.14-2.91). HAE is associated with VTE among young and middle-aged individuals in Swedish families with HAE. The effect size of the association is in the order of other thrombophilias. We suggest that HAE may be considered a new rare thrombophilia.

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Importance: For individuals without a family history of colorectal cancer (CRC), colonoscopy screening every 10 years is recommended to reduce CRC incidence and mortality. However, debate exists about whether and for how long this 10-year interval could be safely expanded. Objective: To assess how many years after a first colonoscopy with findings negative for CRC a second colonoscopy can be performed. Design, Setting, and Participants: This cohort study leveraged Swedish nationwide register-based data to examine CRC diagnoses and CRC-specific mortality among individuals without a family history of CRC. The exposed group included individuals who had a first colonoscopy with findings negative for CRC at age 45 to 69 years between 1990 and 2016. The control group included individuals matched by sex, birth year, and baseline age (ie, the age of their matched exposed individual when the exposed individual's first colonoscopy with findings negative for CRC was performed). Individuals in the control group either did not have a colonoscopy during the follow-up or underwent colonoscopy that resulted in a CRC diagnosis. Up to 18 controls were matched with each exposed individual. Individuals were followed up from 1990 to 2018, and data were analyzed from November 2022 to November 2023. Exposure: A first colonoscopy with findings negative for CRC, defined as a first colonoscopy without a diagnosis of colorectal polyp, adenoma, carcinoma in situ, or CRC before or within 6 months after screening. Main Outcomes and Measures: The primary outcomes were CRC diagnosis and CRC-specific death. The 10-year standardized incidence ratio and standardized mortality ratio were calculated to compare risks of CRC and CRC-specific death in the exposed and control groups based on different follow-up screening intervals. Results: The sample included 110 074 individuals (65 147 females [59.2%]) in the exposed group and 1 981 332 (1 172 646 females [59.2%]) in the control group. The median (IQR) age for individuals in both groups was 59 (52-64) years. During up to 29 years of follow-up of individuals with a first colonoscopy with findings negative for CRC, 484 incident CRCs and 112 CRC-specific deaths occurred. After a first colonoscopy with findings negative for CRC, the risks of CRC and CRC-specific death in the exposed group were significantly lower than those in their matched controls for 15 years. At 15 years after a first colonoscopy with findings negative for CRC, the 10-year standardized incidence ratio was 0.72 (95% CI, 0.54-0.94) and the 10-year standardized mortality ratio was 0.55 (95% CI, 0.29-0.94). In other words, the 10-year cumulative risk of CRC in year 15 in the exposed group was 72% that of the 10-year cumulative risk of CRC in the control group. Extending the colonoscopy screening interval from 10 to 15 years in individuals with a first colonoscopy with findings negative for CRC could miss the early detection of only 2 CRC cases and the prevention of 1 CRC-specific death per 1000 individuals, while potentially avoiding 1000 colonoscopies. Conclusions and Relevance: This cohort study found that for the population without a family history of CRC, the 10-year interval between colonoscopy screenings for individuals with a first colonoscopy with findings negative for CRC could potentially be extended to 15 years. A longer interval between colonoscopy screenings could be beneficial in avoiding unnecessary invasive examinations.

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