INTRODUCTION:Automated cerebrospinal fluid (CSF) biomarker assays have largely replaced manual immunoassays for measuring amyloid pathology in CSF. We refitted and validated the ABIDE model, predicting progression from mild cognitive impairment (MCI) to dementia, with CSF measurements from the automated Elecsys platform. METHODS:We included 2413 MCI participants (998 [41%] amyloid-positive) from seven observational cohorts. Elecsys was used in 958 (40%) participants. The parameters of the previous ABIDE Cox model were re-estimated. Model discrimination and calibration were evaluated with leave-one-cohort-out cross-validation. RESULTS:During follow-up, 1034 (42%; 585 [58%] amyloid-positive) participants developed dementia. Discrimination was good with Harrell's C of 0.70 (95% confidence interval [CI]: 0.66-0.73). Calibration was good in the total population and amyloid-positive subgroup, with substantial predicted progression risks for all amyloid-positive participants. DISCUSSION:We refitted the ABIDE model, predicting MCI to dementia progression, with automated CSF measurements. The model was well calibrated in amyloid-positive patients and may support clinical discussions regarding ATTs.

Prophylactic vaccination is a powerful tool that changes exposure to infections and associated morbidity of preventable diseases. We discuss the impact of pneumococci and human papillomavirus (HPV) vaccination on the population biology of the two micro-organisms and related public health effects. Data on HPV type-replacement in communities where vaccine-covered HPVs are almost eliminated, and interactions of the remaining HPV types on the risk of cervical cancer are reviewed. Results of comprehensive models for European country-specific conduction of cervical screening among HPV-vaccinated and unvaccinated women, assuming different HPV-vaccination coverage and strategies, are discussed in our policy-oriented review. An acceptable balance of benefits and harms of cervical cancer screening in HPV vaccinated populations requires an understanding of cancer risks in differently vaccinated birth cohorts. Finally, the challenges are complex but can be met if strategies are applied that (i) as fast as possible achieve herd effect and (ii) use a risk-based design of HPV screening.

OBJECTIVES:High-grade vulvar intraepithelial neoplasia (VIN) is the precursor of vulvar squamous cell carcinoma (VSCC). High-grade VIN is categorized into human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesion (HSIL) and HPV-independent VIN (HPVi-VIN). This study aimed to comprehensively characterize recurrence in a large VIN cohort with long-term follow-up. METHODS:Recurrence was assessed in 578 HSIL and 46 HPVi-VIN patients by evaluating recurrence risk, number of recurrences, and related diagnostic/excisional procedures. Kaplan-Meier analysis estimated recurrence and VSCC risks, and Cox regression analysis was applied to identify risk factors for recurrence. RESULTS:The median follow-up time was 15 years for HSIL and 5.5 years for HPVi-VIN patients. Recurrence occurred in 50% of HSIL (288/578) and 63% of HPVi-VIN (29/46) patients. Cancer was present at first recurrence in 8.0% of HSIL (23/288) and 45% of HPVi-VIN (13/29). The 5-year recurrence risk was 36% for HSIL and 57% for HPVi-VIN (73% for p53 mutant, 25% for p53 wild-type). Among patients with recurrence, 39% of HSIL and 14% of HPVi-VIN had ≥3 recurrences during follow-up, requiring a median of 6.0 and 5.5 surgical procedures, respectively. For HSIL patients, the 5-year recurrence risk increased to 55% and 57% after the first and second recurrence, respectively, while the 5-year cancer risk increased from 4.5% at initial presentation to 7.4% and 12%, respectively. No independent risk factors for recurrence in HSIL were identified. CONCLUSIONS:Both HSIL and HPVi-VIN patients are at high risk of recurrence, with a higher cancer risk observed in those with recurrent HSIL or those with HPVi-VIN.

Cervical cancer screening in the Netherlands consists of human papillomavirus (HPV) testing followed by cytological triage at age 30, 35, 40, 50, and 60 years. Women are also invited at age 45, 55 and 65 years if they did not test HPV-negative 5 years earlier (risk-based invitation). With influx of birth cohorts vaccinated against HPV, de-intensification may be needed to maintain a cost-effective program. We used an updated and recalibrated model of type-specific HPV transmission and cervical carcinogenesis to estimate the cost-effectiveness of 16 strategies with reduced screening intensity. Strategies varied by starting age, screening interval, and number of risk-based invitations, possibly stratified for HPV vaccination status. Cost-effectiveness was measured by net monetary benefit (NMB). A positive NMB indicates that a strategy is cost-effective compared to the current policy. Two strategies without stratification for HPV vaccination status had a positive NMB. An NMB of EUR 1.6 million per 100,000 women was obtained when, compared to current screening, the invitation at age 35 was based on the HPV-test result at age 30. An NMB of EUR 1.8 million per 100,000 women was obtained when women were re-invited every 5 years if they were HPV-positive or had not been tested 5 years earlier. If reduced screening was only applied to vaccinated women, the highest NMB was EUR 1.3 million per 100,000 women. Thus, reducing screening in HPV-vaccinated cohorts is cost-effective when re-inviting women after 10 years if they test HPV-negative. Stratification for HPV vaccination status does not improve the cost-effectiveness of screening.

Abstract Background Therapy development in ultra-rare, progressive and fatal diseases like vanishing white matter (VWM) is hampered by very low patient numbers and ethical constraints regarding placebo-controlled studies. Under such conditions, standard randomized controlled trials may not be feasible. The use of historical control information could be part of a solution, but would require extra considerations regarding selection of patients and choice of endpoints. We used the VWM registry as a case study to outline key methodological considerations for informing trial design in ultra-rare disease. Methods The study included 462 patients, available in the VWM registry. Prospective clinical data were collected since 2004 using VWM-specific questionnaire and Health Utility Index (HUI) assessments, while retrospective data from clinical charts were available from 1988 on. We evaluated methodological aspects relevant to trial design, including patient selection, drift in the disease course over time, endpoint selection, and clinically relevant stratification into subgroups. Results Regarding patient selection, patients with comorbidities impacting disease course, and pre-symptomatic individuals without clinical onset were considered not suitable as historical controls. After excluding patients before 1991, we found no evidence of drift in the disease course from 1991 onwards. Regarding choice of endpoints, episodes of rapid decline were relatively infrequent and occurred mostly at disease onset, limiting their usefulness as trial endpoint. Multi-state modelling and clinical evaluation showed ambulation as preferable endpoint over survival. For longitudinal HUI multiscores, baseline imputation allowed modelling of early disease. The scores showed a distinct ordering, reflecting the association between multi-domain function and disease progression. Regarding stratification, the combination of data-driven analyses and clinical expertise informed revised age of onset groups. Females showed later onset and milder disease; adjustment for age of onset eliminated the effect of sex. Conclusion This case study provides key considerations for evaluating registry data as historical control and demonstrates how these considerations can inform clinical trial design in ultra-rare diseases.

Introduction. High-grade cervical intraepithelial neoplasia (CIN2/3) exhibit heterogeneous clinical behavior, ranging from spontaneous regression to progression to cancer. Methylation testing of FAM19A4/miR124-2 genes in clinician- and self-collected cervical scrapes has demonstrated to predict clinical regression in women with untreated CIN2/3 (CONCERVE study). This post hoc analysis of the CONCERVE study evaluated the prognostic value of FAM19A4/miR124-2 methylation testing, immunoscore (based on the extent of p16 INK4a and Ki-67 expression), and HPV E4 expression in CIN2/3 biopsies, to predict clinical regression. Methods. CIN2/3 biopsies of 89 women with known HPV genotypes were analyzed by FAM19A4/miR124-2 methylation testing and immunohistochemistry for p16 INK4a , Ki-67 and HPV E4. Association with clinical regression was assessed using univariable and multivariable Cox regression. Regression incidences were estimated using the Kaplan-Meier method. Results. Women with a p16 INK4a block-positive and methylation-negative CIN2/3 biopsy (n = 42) had significantly higher 2-year regression rates (76%; 95% CI: 57.7–86.4) than women with methylation-positive biopsy (n = 33, 44.9%; 95% CI: 23.8–60.1, p = 0.009). This prognostic effect was particularly evident in HPV16-positive women (n = 47), with a 65.9% (95% CI: 32.3–82.9) regression rate in methylation-negative lesions versus 29.5% (95% CI: 0-48.7, p = 0.029) in methylation-positive ones. P16 INK4a /Ki-67 immunoscore and HPV E4 expression were not associated with clinical regression. Conclusions. A negative FAM19A4/miR124-2 methylation test on baseline, p16 INK4a block-positive CIN2/3 biopsies is prognostic for clinical regression, supporting its auxiliary role in personalized management strategies.

DNA methylation analysis of the genes FAM19A4 and miR124-2 has emerged as a promising triage strategy for high-risk (hr) human papillomavirus (HPV)-positive women in cervical screening. This study reports a prospective evaluation of the diagnostic accuracy of FAM19A4/miR124-2 methylation in a large population-based primary HPV-based screening cohort with 18 months of follow-up. In this prospective observational study, clinician-collected cervical samples from 3848 consecutive hrHPV-positive women who participated in the Dutch national primary HPV-based screening program were tested with the QIAsure Methylation Test, a quantitative methylation-specific PCR assessing FAM19A4 and miR124-2 methylation. Through linkage to the Dutch Nationwide Pathology Databank (Palga), 11 cases of cervical carcinoma, 293 cervical intraepithelial neoplasia grade 3 (CIN3), and 29 adenocarcinoma in situ (AIS) were identified during 18 months of follow-up. Clinical performance for CIN3, AIS, and cancer (CIN3+) detection was assessed based on (I) the threshold of the QIAsure Methylation Test, and (II) thresholds corresponding with clinical specificities of 70% and 80% in this hrHPV-positive study population. The sensitivity and specificity of FAM19A4/miR124-2 methylation for CIN3+ detection using the QIAsure Methylation Test threshold (I) were 57.4% (95% CI: 52.0-62.7) and 88.3% (95% CI: 87.2-89.5), respectively. At predefined specificities of 70% and 80%, FAM19A4/miR124-2 methylation (II) demonstrated a CIN3+ sensitivity of 75.4% (95% CI: 70.7-80.0) and 66.1% (95% CI: 61.0-71.2), respectively. In conclusion, FAM19A4/miR124-2 methylation analysis showed good triage performance in a primary HPV-based screening setting. These findings support the use of methylation-based testing as a triage strategy in primary HPV-based screening programs, with an appropriate follow-up policy for hrHPV-positive women who test methylation-negative.

BackgroundOptimizing cancer screening and surveillance frequency requires accurate information on parameters such as sojourn time and cancer risk from premalignant lesions. These parameters can be estimated using multistate cancer models applied to screening or surveillance data. However, the performance of these models has not been thoroughly investigated in settings in which cancer precursors are treated upon detection, preventing progression to cancer. Our main goal is understanding the performance of available multistate methods in this challenging censoring setting.MethodsWe assumed progression hazards between consecutive health states in a 3-state model (healthy [HE], cancer precursor, and cancer) to be either time independent or dependent on time since state entry and compared 6 methods implemented in R software packages with varying assumptions: time-independent hazards (msm), hazards dependent on time since state entry (msm with a phase-type model, cthmm, smms, BayesTSM), and hazards dependent on time since the start of the process (hmm). Risk estimates from each method were compared in simulations and illustrated using colorectal cancer surveillance data from 734 individuals, classified into 3 health states: HE, non-advanced adenoma (nAA), and advanced neoplasia (AN).ResultsAll methods performed well with time-independent hazards in the simulation study. With hazards dependent on time since state entry, only smms and BayesTSM provided unbiased risk estimates. In the application, only msm,hmm, and BayesTSM yielded converged solutions. The nAA risk estimates were similar between hmm and BayesTSM but differed for msm, while AN risk estimates varied across methods.ConclusionsMethods for multistate cancer models, specifically with unobservable precursor-to-cancer transition, are strongly affected by the time dependency of the hazard. With time-dependent hazards since state entry, BayesTSM provided robust estimates, in both the simulation and application.HighlightsThis study presents the first comprehensive comparison of available multistate modeling options for screening and surveillance data, focusing on the specific setting of a 3-state progressive model (healthy, cancer precursor, cancer) in which cancer precursors are treated upon detection so that the transition to cancer is prevented (censoring after intervention). Sample R code and simulated data demonstrating the compared methods, along with documentation (including installation instructions, manual, and/or worked examples) for the corresponding R software packages, are available at https://github.com/EddymurphyAkwiwu/MultiStateMethods.All methods provide unbiased risk estimates for transition times when the true progression hazards are time independent. With more realistic models in which progression hazards are dependent on time since state entry, only BayesTSM and smms yield unbiased risk estimates for transition times.In situations with weakly identifiable likelihoods, the smms package may suffer from numerical and optimization problems. The BayesTSM package overcomes these problems by applying regularized parameter estimation using weakly informative priors.Methods for multistate cancer models, more specifically with unobservable precursor-to-cancer transition, are strongly affected by the time dependency of the hazard. An inappropriate choice can lead to biased parameter estimates.

In 2017, the Netherlands introduced primary human papillomavirus (HPV)-based screening with cytology triage, which increased colposcopy referrals and low-grade lesions detected. In 2022, HPV16/18 genotyping was added for women with borderline/low-grade cytology. Triage with HPV genotyping may better balance screening benefits, harms, and costs. Therefore, we evaluated the cost-effectiveness of 19 triage strategies based on net monetary benefit (NMB) at cost-effectiveness thresholds of €20,000 and €50,000/quality-adjusted life-year (QALY), with the highest NMB indicating the most cost-effective strategy. Triage tests included 16/18 genotyping, 7-type (16/18/31/33/45/52/58) genotyping, and cytology (high-grade squamous intraepithelial lesions [HSIL]: moderate/severe, atypical squamous cells of undetermined significance [ASC-US]/low-grade squamous intraepithelial lesions [LSIL]: borderline/low-grade, negative for intraepithelial lesion or malignancy [NILM]: normal). Effects on cancer incidence and mortality were obtained by combining POBASCAM trial data with nationwide screening and cancer registries. Time since the onset of high-grade lesion (cervical intraepithelial neoplasia [grade 2/3] [CIN2/3]) at baseline of the Population-based Screening Study Amsterdam trial cannot be estimated from the data and was varied between 0 and 10 years. At a €20,000/QALY threshold, immediate referral for HSIL and 16/18-positive ASC-US/LSIL, and repeat cytology for 16/18-negative ASC-US/LSIL and 7-types positive NILM had the highest NMB (€214.1 to €309.3/woman gained compared to referring all HPV-positive women). At a €50,000/QALY threshold, immediate referral for all 16/18-positives and/or HSIL, and repeat cytology for 16/18-negative ASC-US/LSIL and 7-types positive NILM had the highest NMB if time since onset of CIN2/3 was greater than 2 years. Cytology combined with HPV16/18 and extended genotyping is cost-effective for triage of HPV-positives. Immediate colposcopy referral of all HPV16/18-positives is cost-effective at a €50,000/QALY threshold.

High-grade vulvar intraepithelial neoplasia (VIN), the precursor lesion to vulvar cancer, comprises human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesion (HSIL) and HPV-independent VIN (HPVi-VIN), differing in pathogenesis and cancer risk. HSIL typically develops from low-grade squamous intraepithelial lesion (LSIL), and HPVi-VIN from lichen sclerosus (LS). The PreCursor-M AnoGYN Methylation test, targeting ASCL1/ZNF582, may improve diagnostic accuracy and risk stratification in high-grade VIN patients. This study assessed its diagnostic performance to detect high-grade VIN and cancer. ASCL1/ZNF582 methylation was analyzed in 170 vulvar formalin-fixed paraffin-embedded (FFPE) tissue samples from healthy controls, LS, LSIL, HSIL, HPVi-VIN and vulvar cancer patients by quantitative methylation-specific polymerase chain reaction (qMSP). Logistic regression analysis was used to evaluate its diagnostic performance and compare it to the previously established ZNF582/SST/miR124-2 marker panel. Methylation levels increased with disease severity, from low in controls, LS and LSIL to high in HSIL, HPVi-VIN and vulvar cancer. The ASCL1/ZNF582 marker panel detected 92

Background:The protective effect of HPV vaccination against cervical cancer has been demonstrated in registry linkage studies. The start age of screening in those studies was lower than 25 years. We estimated the vaccine effectiveness of bivalent HPV16/18 vaccination against invasive cervical cancer and cervical intraepithelial neoplasia grade 3 (CIN3+) in the Netherlands where routine screening starts at age 30 years. Methods:We linked the vaccination status of women born in year 1993 who were eligible for HPV vaccination at age 16 years with histopathological results recorded in the nationwide pathology databank (Palga). Cumulative risks of invasive cervical cancer and CIN3+ were estimated for fully vaccinated (3 doses or 2 doses ≥150 days apart), partially vaccinated, and unvaccinated women. Vaccine effectiveness estimates were adjusted for differences in screening participation between the vaccine groups. Findings:A total of 103,059 women were included, of whom 47,130 were fully vaccinated, 5,098 were partially vaccinated, and 50,831 were unvaccinated. Five (0·011%) cancers were observed in fully vaccinated, two (0·039%) in partially vaccinated, and 42 (0·083%) in unvaccinated women. The vaccine effectiveness in fully vaccinated women was 91·5% (95% CI 78·9, 96·6) against cancer and 81·2% (95% CI 78·4, 83·7) against CIN3+. The vaccine effectiveness in partially vaccinated women was 48·1% (95% CI -56·8, 82·8) against cancer and 58·4% (95% CI 45·3, 68·3) against CIN3+. Interpretation:The high effectiveness of bivalent HPV vaccination against cervical cancer and CIN3+ and the low cancer incidence supports a screening start age of 30 years in vaccinated women. Research in context:Evidence before this study: We searched Pubmed and Google Scholar with the search terms ("Cervical Cancer") AND ("HPV" OR "human papillomavirus") AND ("vaccination"). Articles published in English were searched until January 2, 2025. Studies from Sweden, Denmark, and Scotland were identified linking individual vaccination, screening and cancer registry data. The start age of screening in these studies was 23-25 years. They showed a strong effectiveness in preventing cervical cancer following the introduction of bivalent and quadrivalent HPV vaccination.Added value of this study: We observed a very low absolute incidence of cervical cancer in vaccinated women and a much lower incidence of cervical cancer and CIN3+ in women vaccinated at age 16 compared with unvaccinated women, in a setting where routine screening starts at age 30. By linking the vaccination registry to the nationwide pathology databank, we were able to adjust for screening non-attendance in the incidence of cancer and CIN3+ over a 15 year period.Implications of all the available evidence: Our study supports a start age of screening of at least 30 years in women vaccinated at a young age. Avoiding screening before age 30 in these women is expected to substantially reduce the harms associated with screening and treatment.

To optimize colorectal cancer (CRC) surveillance, accurate information on the risk of developing CRC from premalignant lesions is essential. However, directly observing this risk is challenging since precursor lesions, that is, advanced adenomas (AAs), are removed upon detection. Statistical methods for multistate models can estimate risks, but estimation is challenging due to low CRC incidence. We propose an outcome-dependent sampling (ODS) design for this problem in which we oversample CRCs. More specifically, we propose a 3-state model for jointly estimating the time distributions from baseline colonoscopy to AA and from AA onset to CRC accounting for the ODS design using a weighted likelihood approach. We applied the methodology to a sample from a Norwegian adenoma cohort (1993-2007), comprising 1495 individuals (median follow-up $6.8$ years; IQR, 1.1-12.8) of whom 648 did and 847 did not develop CRC. We observed a 5-year AA risk of 13% and 34% for individuals having nonadvanced adenoma (NAA) and AA removed at baseline colonoscopy, respectively. Upon AA development, the subsequent risk to develop CRC in 5 years was 17% and age-dependent. These estimates provide a basis for optimizing surveillance intensity and determining the optimal trade-off between CRC prevention, costs, and use of colonoscopy resources.

Accurate risk assessment is essential for screening and surveillance programs, but this is complicated when considering baseline conditions linked to an increased risk of disease that may decline over time (e.g., certain infections and viral-induced disease). In longitudinal screening and surveillance studies, individuals may have prevalent disease at baseline or develop it during follow-up, either from their baseline condition ("early" event) or from a new condition ("late" event). Additionally, data are interval-censored between visits, making the exact time of disease onset unknown. We propose a prevalence-incidence-clearance model for interval-censored data to estimate cumulative disease risk based on individual risk factors, with the motivating example of human papillomavirus (HPV) infections, which may progress to high-grade cervical lesions and cancer (CIN2+). Early events are modelled with an exponential competing risks framework, where HPV infections either progress to CIN2+ or to a (latent) "clearance" state. Late events are modelled by adding a background risk. Parameters are estimated with an expectation-maximisation algorithm with weakly informative Cauchy priors. The algorithm was validated through simulation studies and applied to screening and post-treatment surveillance data from the Netherlands. Our model accurately predicts cumulative CIN2+ risk in HPV-positive women and fits the observed cumulative incidence curve better than existing methods. Furthermore, it provides easily interpretable parameters and its baseline hazard can be checked for lack of fit. This is especially important when applying the model to facilitate decision-making for national programs. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Horizon 2020 research and innovation program of the European Commission \[RISCC project, grant agreement No 847845\] (to KRK, JAB, CJLMM, and JB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The POBASCAM trial (Trial registration ID: NTR218) was approved by the Medical Ethics Committee of the Vrije Universiteit (VU) University Medical Centre (Amsterdam, The Netherlands; no. 96/103) and the Ministry of Public Health (The Hague, The Netherlands; VWS no. 328650). All participants provided written informed consent. The post-treatment cohort study (Trial registration ID: NTR1468) was approved by the ethics board at all hospitals. All women provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author upon reasonable request. The code for the accompanying R package is publicly available on GitHub (https://github.com/kelsikroon/PICmodel).

Background:The protective effect of HPV vaccination against cervical cancer has been demonstrated in registry linkage studies. The start age of screening in those studies was lower than 25 years. We aimed to estimate the effectiveness of bivalent HPV16/18 vaccination against invasive cervical cancer and cervical intraepithelial neoplasia grade 3 (CIN3+) in the Netherlands, where routine screening starts at age 30 years. Methods:We linked the vaccination status of women born in 1993 who were eligible for HPV vaccination at age 16 years with histopathological results recorded until April 1, 2024, in the nationwide pathology databank (Palga). Cumulative risks of invasive cervical cancer and CIN3+ were estimated for fully vaccinated (3 doses or 2 doses ≥150 days apart), partially vaccinated, and unvaccinated women. Cumulative risk ratios (CRRs) were adjusted for differences in screening participation between vaccine groups. Findings:A total of 103,059 women were included, of whom 47,130 were fully vaccinated, 5098 partially vaccinated, and 50,831 unvaccinated. Five cancers (0·011%) were observed in fully vaccinated, two (0·039%) in partially vaccinated, and 42 (0·083%) in unvaccinated women. The CRR for fully vaccinated women compared with unvaccinated women was 0·085 (95% confidence interval 0·025, 0·24) for cancer and 0·19 (0·16, 0·23) for CIN3+. The CRR for partially vaccinated women was 0·52 (0·12, 1·71) for cancer and 0·42 (0·30, 0·57) for CIN3+. Interpretation:The risk of cervical cancer and CIN3+ was strongly reduced in vaccinated women indicating that vaccine protection extends at least until age 30. Funding:The Dutch Ministry of Health, Welfare, and Sport.

Supplementary Table 1: Birthyears invited for screening in 2017 and 2018. Supplementary Figure 1: Data linkage flowchart, describing how CBS data was linked to PALGA data on an individual level

INTRODUCTION:To address uncertainty about long-term clinical and economic impacts of an accurate dementia diagnosis, we evaluated the cost-effectiveness of adding amyloid positron emission tomography (PET) to memory clinic workup over 5 years. METHODS:Inverse probability weighting was used to balance covariates between PET (n = 440) and no-PET (n = 460) participants from the Amsterdam Dementia Cohort. Time in community following diagnosis, time alive, and costs were combined in cost-effectiveness analyses. RESULTS:PET participants lived longer in community (0.26 years, 95% confidence interval [CI]: 0.05 to 0.45) and overall (0.15, CI: 0.02 to 0.27), but did not have statistically different health insurance (€703, CI: -3974 to 5045) or total costs including institutionalization (-€8258, CI: -20,622 to 3377). The probability that PET was cost-effective for extending time in community was 76% at a €2530 willingness-to-pay threshold. The probability that PET yielded cost savings and was more effective for extending time alive was 90%. DISCUSSION:Findings in this observational cohort suggest that using amyloid PET in memory clinics may be cost-effective. Highlights:Participants with an amyloid PET in a memory clinic work-up were compared to those without.The amyloid PET group spent more time in community and alive over 5 years of follow-up.Amyloid PET had a 76% chance to cost-effectively extend time in community in uncertainty analysis.

We hypothesise that improved diagnostic precision, operationalised by adding amyloid positron emission tomography (PET) to the diagnostic work-up in a memory clinic, is beneficial for long-term health and healthcare cost outcomes. We investigated whether a more precise diagnosis influenced institutionalisation and mortality incidence trajectories, and annual healthcare costs over a period up to eight years. Between October 2014 and December 2016, patients from the Amsterdam Dementia Cohort were offered an amyloid-PET as part of their diagnostic work-up. Those who received an amyloid-PET were propensity-score matched to participants without a PET, creating two balanced groups containing 442 patients each (Table 1; 64±8yrs, 40%F, 43% dementia). Statistics Netherlands provided healthcare costs for six years, institutionalisation for seven years, and mortality data for eight years of follow-up. Institutionalisation and mortality incidence were calculated, and mean costs were bootstrapped. Healthcare costs were first evaluated as annual total cost and subsequently disaggregated into the following categories: primary care, hospital-related care, mental health care, aid products, medication, homecare, and institutionalisation. The amyloid-PET and no-PET groups had distinct institutionalisation and mortality incidence trajectories (Figure 1). The difference in institutionalisation was most pronounced three years after the diagnosis with 11% institutionalisation in the amyloid-PET group (95% confidence interval [CI]: 8%-14%, n=50), compared to 20% in the no-PET group (15%-25%, n=95, p=0.002). Subsequently, the difference attenuated to 28% (24%-33%, n=118) vs. 33% (27%-38%, n=135, p=0.28) after six years. Mortality incidences started to converge after four and merged after six years. Annual healthcare costs were €3968 (CI:1177-6942, Table 2) lower in the amyloid-PET group. This difference was mostly attributable to the categories of institutionalisation costs (€-3361; CI:-5929 to -918) and primary care (€-99; CI:-195 to -7). A more precise diagnosis through an amyloid-PET positively influenced the incidence trajectories of institutionalisation and mortality, with the largest differences observed in the first three to four year after the diagnosis. Our findings suggest a more precise diagnosis could lead to more efficient and tailored primary care and to postponed institutionalisation. Less time spent in institutional care was also identified as a main driver of lower healthcare costs.

BACKGROUND:The impact of human papillomavirus (HPV) vaccination programs depends on the degree of indirect protection against new infections achieved among unvaccinated women. We estimated the indirect effect of bivalent HPV vaccination by comparing the HPV-type incidence in unvaccinated female participants between a cohort offered vaccination in 2009/2010 and a cohort of similar-aged women offered vaccination in 2014. METHODS:We compared the incidence rates of HPV types in the HAVANA cohort (follow-up from 2010/2011 until 2015/2016) with those from the HAVANA-2 cohort (2017-2022) using two regression approaches to estimate the indirect effect of HPV vaccination. First, we calculated the incidence ratio (IRR) for a vaccine or cross-protective type in HAVANA-2 versus HAVANA by Poisson regression and compared it to the IRR for a non-cross-protective type. The indirect vaccine effect is defined as 1-ratio of the IRRs. Second, we performed Cox regression with infection by vaccine or cross-protective type as the endpoint and calculated the hazard ratio (HR) for HAVANA-2 versus HAVANA after adjusting for time-varying sociodemographic variables. The indirect effect is defined as 1-HR. RESULTS:We included 661 unvaccinated participants in HAVANA and 927 in HAVANA-2. We observed a significant reduction in incident HPV16 infections of 70.9% (95% CI 48.3-83.7%) with Poisson regression and of 73.1% (95% CI 53.3-84.5%) with Cox regression. For HPV45, significant decreases of 67.3% (95% CI 8.8-88.3%) and 69.8% (95% CI 15.2-89.3%) were observed. For HPV18, HPV31, and HPV33, the indirect effect was not statistically significant. CONCLUSIONS:Large indirect effects of the bivalent HPV vaccination program were observed for HPV16 and HPV45 infections.

BACKGROUND:Amyloid positron emission tomography (PET) is instrumental in achieving an accurate diagnosis and may help to limit health-seeking behavior. Currently, amyloid-PET is not routinely used in clinical practice due to lack of evidence on cost-utility. We assessed the cost-utility of early versus no amyloid-PET in the diagnostic work-up of memory clinic patients after 6 months. METHODS:We assessed cost-utility of patients enrolled in AMYPAD-DPMS (EudraCT Number: 2017-002527-21) from six European memory clinics and randomized in ARM1; early amyloid-PET, ARM2; no amyloid-PET or ARM3; (amyloid-PET at request of the managing physician). ARM3 was not part of the cost-utility analysis. The EuroQol classification system (EQ-5D-5L), visual analogue scale (VAS), and ICEpop Capability measure for older people (ICECAP-O) were collected at baseline and 6 months. Costs were calculated from cost diaries at baseline, 3 and 6 months. The incremental cost-effectiveness ratio (ICER) was calculated using EQ-5D-5L and a societal perspective. RESULTS:From April 2018, to October 2020, 844 participants were screened and 840 were randomized (290 ARM1; 270 ARM2 and 280 ARM3). N = 514 (250 ARM1; 264 ARM2) were included in the economic evaluation. Amyloid-PET resulted in higher costs at 6 months (ARM1 vs. ARM2 ∆€1384, bootstrapped 95% CI [7, 2761]). No significant difference in EQ-5D-5L, VAS or ICECAP-O was found. The incremental cost-effectiveness ratio (ICER) was €461,333 per QALY. CONCLUSION:Although patients receive an early etiological diagnosis, the cost-utility after 6 months is not favorable for amyloid-PET. The cost-utility will need to be reassessed when considering amyloid-PET to select patients for anti-amyloid biologics.