A new approach of nonparametric estimation of incidence and lifetime risk based on birth rates and incident events

<p>Abstract</p> <p>Background</p> <p>Incidence and lifetime risk of diabetes are important public health measures. Traditionally, nonparametric estimates are obtained from survey data by means of a Nelson-Aalen estimator which requires data information on both incident events and risk sets from the entire cohort. Such data information is rarely available in real studies.</p> <p>Methods</p> <p>We compare two different approaches for obtaining nonparametric estimates of age-specific incidence and lifetime risk with emphasis on required assumptions. The first and novel approach only considers incident cases occurring within a fixed time window–we have termed this <it>cohort-of-cases </it>data–which is linked explicitly to the birth process in the past. The second approach is the usual Nelson-Aalen estimate which requires knowledge on observed time at risk for the entire cohort and their incident events. Both approaches are used on data on anti-diabetic medications obtained from Odense Pharmacoepidemiological Database, which covers a population of approximately 470,000 over the period 1993–2003. For both methods we investigate if and how incidence rates can be projected.</p> <p>Results</p> <p>Both the new and standard method yield similar sigmoidal shaped estimates of the cumulative distribution function of age-specific incidence. The Nelson-Aalen estimator gives somewhat higher estimates of lifetime risk (15.65% (15.14%; 16.16%) for females, and 17.91% (17.38%; 18.44%) for males) than the estimate based on cohort-of-cases data (13.77% (13.74%; 13.81%) for females, 15.61% (15.58%; 15.65%) for males). Accordingly the projected incidence rates are higher based on the Nelson-Aalen estimate–also too high when compared to observed rates. In contrast, the cohort-of-cases approach gives projections that fit observed rates better.</p> <p>Conclusion</p> <p>The developed methodology for analysis of cohort-of-cases data has potential to become a cost-effective alternative to a traditional survey based study of incidence. To allow more general use of the methodology, more research is needed on how to relax stationarity assumptions.</p

Trends in cause-specific mortality among people with type 2 and type 1 diabetes from 2002 to 2019:A Danish population-based study

BackgroundDespite advances in primary and secondary prevention of cardiovascular disease,excess mortality persists within the diabetes population. This study explores thecomponents of this excess mortality and their interaction with sex.MethodsUsing Danish registries (2002-2019), we identified residents aged 18-99 years, theirdiabetes status, and recorded causes of death. Applying Lexis-based methods, wecomputed age-standardized mortality rates (asMRs), mortality relative risks (asMRRs),and log-linear trends for cause-specific mortality.FindingsFrom 2002-2019, 958,278 individuals died in Denmark (T2D: 148,620; T1D: 7,830)during 84.4M person-years. During the study period, overall asMRs declined, driven byreducing cardiovascular mortality, notably in men with T2D. Conversely, cancermortality remained high, making cancer the leading cause of death in individuals withT2D. Individuals with T2D faced an elevated mortality risk from nearly all cancer types,ranging from 9% to 257% compared to their non-diabetic counterparts. Notably,obesity-related cancers exhibited the highest relative risks: liver cancer (Men: asMRR3·58(3·28;3·91); Women: asMRR 2·49(2·14;2·89)), pancreatic cancer (Men: asMRR3·50(3·25;3·77); Women: asMRR 3·57(3·31;3·85)), and kidney cancer (Men: asMRR2·10(1·84;2·40); Women: asMRR 2·31(1·92;2·79)). In men with type 2 diabetes, excessmortality remained stable, except for dementia. In women, diabetes-related excessmortality increased by 6-17% per decade across all causes of death, exceptcardiovascular disease.InterpretationIn the last decade, cancer has emerged as the leading cause of death amongindividuals with T2D in Denmark, emphasizing the need for diabetes managementstrategies incorporating cancer prevention. A sex-specific approach is crucial toaddress persistently higher relative mortality in women with diabetes.FundingSupported by Steno Diabetes Center Aarhus, which is partially funded by anunrestricted donation from the Novo Nordisk Foundation, and by The Danish DiabetesAcademy.<br/

Dependency Tree Automata

Abstract. We introduce a new kind of tree automaton, a dependency tree automaton, that is suitable for deciding properties of classes of terms with binding. Two kinds of such automaton are defined, nondeterministic and alternating. We show that the nondeterministic automata have a decidable nonemptiness problem and leave as an open question whether this is true for the alternating version. The families of trees that both kinds recognise are closed under intersection and union. To illustrate the utility of the automata, we apply them to terms of simply typed lambda calculus and provide an automata-theoretic characterisation of solutions to the higher-order matching problem

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence:the randomized phase 2a TITAN trial

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .</p

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756