Shortening the Alzheimer's disease assessment scale cognitive subscale.

BACKGROUND: A short yet reliable cognitive measure is needed that separates treatment and placebo for treatment trials for Alzheimer's disease. Hence, we aimed to shorten the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and test its use as an efficacy measure. METHODS: Secondary data analysis of participant-level data from five pivotal clinical trials of donepezil compared with placebo for Alzheimer's disease (N = 2,198). Across all five trials, cognition was appraised using the original 11-item ADAS-Cog. Statistical analysis consisted of sample characterization, item response theory (IRT) to identify an ADAS-Cog short version, and mixed models for repeated-measures analysis to examine the effect sizes of ADAS-Cog change on the original and short versions in the placebo versus donepezil groups. RESULTS: Based on IRT, a short ADAS-Cog was developed with seven items and two response options. The original and short ADAS-Cog correlated at baseline and at weeks 12 and 24 at 0.7. Effect sizes based on mixed modeling showed that the short and original ADAS-Cog separated placebo and donepezil comparably (ADAS-Cog original ES = 0.33, 95% CI = 0.29, 0.40, ADAS-Cog short ES = 0.25, 95% CI =0.23, 0.34). CONCLUSIONS: IRT identified a short ADAS-cog version that separated donepezil and placebo, suggesting its clinical potential for assessment and treatment monitoring.

Public health-focused use of COVID-19 rapid antigen and PCR tests.

During the Covid-19 pandemic, accurate PCR tests were augmented by the cheap, rapid, and logistically convenient, yet less sensitive antigen tests. In Israel, a testing policy shift was implemented due to limited availability of PCR tests during the Omicron surge. Thus, both PCR and antigen tests were used, as this was the only alternative for mass testing and surveillance at the time. Yet, evidence-based surveillance requires a robust understanding of the expected consequences of changing the testing policy. Using 41,065 paired tests performed by trained staff between January and April 2022 in Israel, we estimate how the sensitivity of antigen tests changes as a function of Ct value and other key covariates. The results reveal a logarithmic relationship between antigen detection probability and viral load, as quantified by Ct-values of the PCR tests. Further analysis shows a statistically significant association with an odds ratio of approximately 0.76 with each unit of Ct-value. The analysis suggests that in spite of their compromised sensitivity, antigen tests are a natural solution for routine use, while PCR tests should be considered in situations where a false negative result could have serious consequences. These findings are the foundations of policies that will utilize the strengths of the different tests, and achieve enhanced hybrid surveillance.

Measuring vaccine protection when the population is mostly vaccinated.

OBJECTIVES: This study aims to address limitations in assessing vaccine protection using the classical vaccine effectiveness (VE) measure, especially in contexts where a significant portion of the population is already vaccinated or infected. STUDY DESIGN AND SETTING: We propose using the adjusted number of cases (ANC) as a building block for deriving vaccine effectiveness measures. This approach accounts for biases arising from small and unrepresentative unvaccinated reference groups with incomplete data. We demonstrate the use of these measures for assessing the protection conferred by a booster dose against severe COVID-19 using data from Israel. RESULTS: The use of ANC and the derived measures reveals a more comprehensive understanding of the complex immunity landscape compared to traditional VE measures. This approach enables meaningful comparisons between different vaccination categories and provides insights to inform policy decisions. CONCLUSION: In situations with widespread vaccination and prior infections, traditional VE measures can be limited in their informative value. Using the ANC offers a more robust and insightful assessment of vaccine effectiveness. A demonstration of the evaluation of booster dose protection against severe COVID-19 in Israel underscores the importance of adopting complementary measures to guide public health strategies.

Protection against Omicron BA.1/BA.2 severe disease 0-7 months after BNT162b2 booster.

Following evidence of waning immunity against both infection and severe disease after 2 doses of the BNT162b2 vaccine, Israel began administering a 3rd BNT162b2 dose (booster) in July 2021. Recent studies showed that the 3rd dose provides a much lower protection against infection with the Omicron variant compared to the Delta variant and that this protection wanes quickly. However, there is little evidence regarding the protection of the 3rd dose against Omicron (BA.1/BA.2) severe disease. In this study, we estimate the preservation of immunity from severe disease up to 7 months after receiving the booster dose. We calculate rates of severe SARS-CoV-2 disease between groups of individuals aged 60 and above, comparing those who received two doses at least 4 months previously to those who received the 3rd dose (stratified by the time from vaccination), and to those who received a 4th dose. The analysis shows that protection conferred by the 3rd dose against Omicron severe disease did not wane over a 7-month period. Moreover, a 4th dose further improved protection, with a severe disease rate approximately 3-fold lower than in the 3-dose cohorts.

Rates of Spontaneous Abortion in Israel Before and During the COVID-19 Pandemic.

This cross-sectional study uses electronic health record data to compare monthly incidence rates of spontaneous abortion in Israel before and during the COVID-19 pandemic.

Increased incident rates of antidepressant use during the COVID-19 pandemic: interrupted time-series analysis of a nationally representative sample.

BACKGROUND: The COVID-19 pandemic has been associated with increased levels of depression and anxiety with implications for the use of antidepressant medications. METHODS: The incident rate of antidepressant fills before and during the COVID-19 pandemic were compared using interrupted time-series analysis followed by comprehensive sensitivity analyses on data derived from electronic medical records from a large health management organization providing nationwide services to 14% of the Israeli population. The dataset covered the period from 1 January 2013 to 1 February 2021, with 1 March 2020 onwards defined as the period of the COVID-19 pandemic. Forecasting analysis was implemented to test the effect of the vaccine roll-out and easing of social restrictions on antidepressant use. RESULTS: The sample consisted of 852 233 persons with a total antidepressant incident fill count of 139 535.4 (total cumulative rate per 100 000 = 16 372.91, 95% CI 16 287.19-16 459.01). We calculated the proportion of antidepressant prescription fills for the COVID-19 period, and the counterfactual proportion for the same period, assuming COVID-19 had not occurred. The difference in these proportions was significant [Cohen's h = 10-3 (0.16), 95% CI 10-3 ( - 0.71 to 1.03)]. The pandemic was associated with a significant increase in the slope of the incident rate of antidepressant fills (slope change = 0.01, 95% CI 0.00-0.03; p = 0.04) and a monthly increase of 2% compared to the counterfactual (the estimated rate assuming no pandemic occurred). The increased rate was more pronounced in women, and was not modified by lockdown on/off periods, socioeconomic or SARS-CoV-2 status. The rate of observed antidepressant fills was similar to that forecasted under the assumption of ongoing COVID-19 distress. CONCLUSION: These findings underscore the toll of the pandemic on mental health and inform mental health policy and service delivery during and after implementing COVID-19 attenuation strategies.

Initial protection against SARS-CoV-2 omicron lineage infection in children and adolescents by BNT162b2 in Israel: an observational study.

BACKGROUND: The BNT162b2 (Pfizer-BioNTech) two-dose vaccine regiment for children and the BNT162b2 third dose for adolescents were approved shortly before the SARS-CoV-2 omicron (B.1.1.529) outbreak in Israel. We aimed to estimate the effects of these vaccines on the rates of confirmed infection against the omicron variant in children and adolescents. METHODS: In this observational cohort study, we extracted data for the omicron-dominated (sublineage BA.1) period. We compared rates of confirmed SARS-CoV-2 infection between children aged 5-10 years 14-35 days after receiving the second vaccine dose with an internal control group of children 3-7 days after receiving the first dose (when the vaccine is not yet effective). Similarly, we compared confirmed infection rates in adolescents aged 12-15 years 14-60 days after receiving a booster dose with an internal control group of adolescents 3-7 days after receiving the booster dose. We used Poisson regression, adjusting for age, sex, socioeconomic status, calendar week, and exposure. FINDINGS: Between Dec 26, 2021, and Jan 8, 2022, we included 1 158 289 participants. In children aged 5-10 years, the adjusted rate of confirmed infection was 2·3 times (95% CI 2·0-2·5) lower in children who received a second dose than in the internal control group. The adjusted infection rate in children who received a second dose was 102 infections per 100 000 risk-days (94-110) compared with 231 infections per 100 000 risk-days (215-248) in the corresponding internal control cohort. In adolescents aged 12-15 years, the booster dose decreased confirmed infection rates by 3·3 times (2·8-4·0) compared with in the internal control group. The adjusted infection rate of the booster cohort was 70 per 100 000 risk-days (60-81) compared with 232 per 100 000 risk-days (212-254) in the internal control cohort. INTERPRETATION: A recent two-dose vaccination regimen with BNT162b2 and a recent booster dose in adolescents substantially reduced the rate of confirmed infection compared with the internal control groups. Future studies are needed to assess the duration of this protection and protection against other outcomes such as paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 and long-COVID. FUNDING: None.

Attempted suicide rates before and during the COVID-19 pandemic: interrupted time series analysis of a nationally representative sample.

BACKGROUND: To characterize the association between the protracted biopsychosocial coronavirus disease 2019 (COVID-19) pandemic exposures and incident suicide attempt rates. METHODS: Data were from a nationally representative cohort based on electronic health records from January 2013 to February 2021 (N = 852 233), with an interrupted time series study design. For the primary analysis, the effect of COVID-19 pandemic on incident suicide attempts warranting in-patient hospital treatment was quantified by fitting a Poisson regression and modeling the relative risk (RR) and the corresponding 95% confidence intervals (CIs). Scenarios were forecast to predict attempted suicide rates at 10 months after social mitigation strategies. Fourteen sensitivity analyses were performed to test the robustness of the results. RESULTS: Despite the increasing trend in the unexposed interval, the interval exposed to the COVID-19 pandemic was statistically significant (p < 0.001) associated with a reduced RR of incident attempted suicide (RR = 0.63, 95% CI 0.52-0.78). Consistent with the primary analysis, sensitivity analysis of sociodemographic groups and methodological factors were statistically significant (p < 0.05). No effect modification was identified for COVID-19 lockdown intervals or COVID-19 illness status. All three forecast scenarios at 10 months projected a suicide attempt rate increase from 12.49 (7.42-21.01) to 21.38 (12.71-35.99). CONCLUSIONS: The interval exposed to the protracted mass social trauma of the COVID-19 pandemic was associated with a lower suicide attempt rate compared to the unexposed interval. However, this trend is likely to reverse 10 months after lifting social mitigation policies, underscoring the need for enhanced implementation of public health policy for suicide prevention.

Opioid Exposure and the Risk of Dementia: A National Cohort Study.

OBJECTIVES: To examine the association between prescription opioid use and the risk of dementia in old-age, since existing studies of the association are few, and the evidence is inconsistent. DESIGN: Prospective national cohort study (N = 91,307, aged 60 years and over), without a dementia diagnosis for ten years, followed-up for incident dementia from January 2013 to October 2017. MEASUREMENTS: Opioid exposure was based on opioid purchases classified from Anatomical Therapeutic Chemical Classification system codes (N02A), and classified as exposed if the purchase period covered at least 60 days within a 120-day interval; otherwise, unexposed. SETTING: Healthcare maintenance organization in Israel. RESULTS: During follow-up, 2,849 (3.1%) persons were opioid exposed (mean age 73.94 ± 6.71 years), and 5,298 (5.8 %) persons developed dementia (mean age 78.07 ± 6.54 years). Cox regression models were fitted to quantify the risk of incident dementia with Hazard Ratios (HR) and their associated 95% Confidence Intervals (CI). The opioid exposed group aged 75+ to 80 years were at an increased risk of incident dementia (Adjusted HR = 1.39, 95% CI = 1.01, 1.92, Z-statistic = 2.02, p <0.05) compared to the unexposed. The point-precision estimates were generally similar to the primary analysis across fourteen sensitivity analyses. CONCLUSION: Policymakers, caregivers, patients, and clinicians may wish to consider that opioid exposure aged 75-80 is linked with an increased dementia risk to balance the potential benefits and adverse side effects of opioid use in old age.

Effect size quantification for interrupted time series analysis: implementation in R and analysis for Covid-19 research.

BACKGROUND: Interrupted time series (ITS) analysis is a time series regression model that aims to evaluate the effect of an intervention on an outcome of interest. ITS analysis is a quasi-experimental study design instrumental in situations where natural experiments occur, gaining popularity, particularly due to the Covid-19 pandemic. However, challenges, including the lack of a control group, have impeded the quantification of the effect size in ITS. The current paper proposes a method and develops a user-friendly R package to quantify the effect size of an ITS regression model for continuous and count outcomes, with or without seasonal adjustment. RESULTS: The effect size presented in this work, together with its corresponding 95% confidence interval (CI) and P-value, is based on the ITS model-based fitted values and the predicted counterfactual (the exposed period had the intervention not occurred) values. A user-friendly R package to fit an ITS and estimate the effect size was developed and accompanies this paper. To illustrate, we implemented a nation population-based ITS study from January 2001 to May 2021 covering the all-cause mortality of Israel (n = 9,350 thousand) to quantify the effect size of Covid-19 exposure on mortality rates. In the period unexposed to the Covid-19 pandemic, the mortality rate decreased over time and was expected to continue decreasing had Covid-19 not occurred. In contrast, the period exposed to the Covid-19 pandemic was associated with an increased all-cause mortality rate (relative risk = 1.11, 95% CI = 1.04, 1.18, P < 0.001). CONCLUSION: For the first time, the effect size in ITS: was quantified, can be estimated by end-users with an R package we developed, and was demonstrated with data showing an increase in mortality following the Covid-19 pandemic. ITS effect size reporting can assist public health policy makers in assessing the magnitude of the entire intervention effect using a single, readily understood measure.

Self-reporting and screening: Data with right-censored, left-censored, and complete observations.

We consider survival data that combine three types of observations: uncensored, right-censored, and left-censored. Such data arises from screening a medical condition, in situations where self-detection arises naturally. Our goal is to estimate the failure-time distribution, based on these three observation types. We propose a novel methodology for distribution estimation using both semiparametric and nonparametric techniques. We then evaluate the performance of these estimators via simulated data. Finally, as a case study, we estimate the patience of patients who arrive at an emergency department and wait for treatment. Three categories of patients are observed: those who leave the system and announce it, and thus their patience time is observed; those who get service and thus their patience time is right-censored by the waiting time; and those who leave the system without announcing it. For this third category, the patients' absence is revealed only when they are called to service, which is after they have already left; formally, their patience time is left-censored. Other applications of our proposed methodology are discussed.

Protection and Waning of Natural and Hybrid Immunity to SARS-CoV-2.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provides natural immunity against reinfection. Recent studies have shown waning of the immunity provided by the BNT162b2 vaccine. The time course of natural and hybrid immunity is unknown. METHODS: Using the Israeli Ministry of Health database, we extracted data for August and September 2021, when the B.1.617.2 (delta) variant was predominant, on all persons who had been previously infected with SARS-CoV-2 or who had received coronavirus 2019 vaccine. We used Poisson regression with adjustment for confounding factors to compare the rates of infection as a function of time since the last immunity-conferring event. RESULTS: The number of cases of SARS-CoV-2 infection per 100,000 person-days at risk (adjusted rate) increased with the time that had elapsed since vaccination with BNT162b2 or since previous infection. Among unvaccinated persons who had recovered from infection, this rate increased from 10.5 among those who had been infected 4 to less than 6 months previously to 30.2 among those who had been infected 1 year or more previously. Among persons who had received a single dose of vaccine after previous infection, the adjusted rate was low (3.7) among those who had been vaccinated less than 2 months previously but increased to 11.6 among those who had been vaccinated at least 6 months previously. Among previously uninfected persons who had received two doses of vaccine, the adjusted rate increased from 21.1 among those who had been vaccinated less than 2 months previously to 88.9 among those who had been vaccinated at least 6 months previously. CONCLUSIONS: Among persons who had been previously infected with SARS-CoV-2 (regardless of whether they had received any dose of vaccine or whether they had received one dose before or after infection), protection against reinfection decreased as the time increased since the last immunity-conferring event; however, this protection was higher than that conferred after the same time had elapsed since receipt of a second dose of vaccine among previously uninfected persons. A single dose of vaccine after infection reinforced protection against reinfection.

The role of statisticians in the response to COVID-19 in Israel: a holistic point of view.

The COVID-19 pandemic cast a dramatic spotlight on the use of data as a fundamental component of good decision-making. Evaluating and comparing alternative policies required information on concurrent infection rates and insightful analysis to project them into the future. Statisticians in Israel were involved in these processes early in the pandemic in some silos as an ad-hoc unorganized effort. Informal discussions within the statistical community culminated in a roundtable, organized by three past presidents of the Israel Statistical Association, and hosted by the Samuel Neaman Institute in April 2021. The meeting was designed to provide a forum for exchange of views on the profession's role during the COVID-19 pandemic, and more generally, on its influence in promoting evidence-based public policy. This paper builds on the insights and discussions that emerged during the roundtable meeting and presents a general framework, with recommendations, for involving statisticians and statistics in decision-making.

Protection by a Fourth Dose of BNT162b2 against Omicron in Israel.

BACKGROUND: On January 2, 2022, Israel began administering a fourth dose of BNT162b2 vaccine to persons 60 years of age or older. Data are needed regarding the effect of the fourth dose on rates of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and of severe coronavirus disease 2019 (Covid-19). METHODS: Using the Israeli Ministry of Health database, we extracted data on 1,252,331 persons who were 60 years of age or older and eligible for the fourth dose during a period in which the B.1.1.529 (omicron) variant of SARS-CoV-2 was predominant (January 10 through March 2, 2022). We estimated the rate of confirmed infection and severe Covid-19 as a function of time starting at 8 days after receipt of a fourth dose (four-dose groups) as compared with that among persons who had received only three doses (three-dose group) and among persons who had received a fourth dose 3 to 7 days earlier (internal control group). For the estimation of rates, we used quasi-Poisson regression with adjustment for age, sex, demographic group, and calendar day. RESULTS: The number of cases of severe Covid-19 per 100,000 person-days (unadjusted rate) was 1.5 in the aggregated four-dose groups, 3.9 in the three-dose group, and 4.2 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of severe Covid-19 in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 3.5 (95% confidence interval [CI], 2.7 to 4.6) and was lower than that in the internal control group by a factor of 2.3 (95% CI, 1.7 to 3.3). Protection against severe illness did not wane during the 6 weeks after receipt of the fourth dose. The number of cases of confirmed infection per 100,000 person-days (unadjusted rate) was 177 in the aggregated four-dose groups, 361 in the three-dose group, and 388 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of confirmed infection in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 2.0 (95% CI, 1.9 to 2.1) and was lower than that in the internal control group by a factor of 1.8 (95% CI, 1.7 to 1.9). However, this protection waned in later weeks. CONCLUSIONS: Rates of confirmed SARS-CoV-2 infection and severe Covid-19 were lower after a fourth dose of BNT162b2 vaccine than after only three doses. Protection against confirmed infection appeared short-lived, whereas protection against severe illness did not wane during the study period.

Protection following BNT162b2 booster in adolescents substantially exceeds that of a fresh 2-dose vaccine.

Israel began administering a BNT162b2 booster dose to restore protection following the waning of the 2-dose vaccine. Biological studies have shown that a "fresh" booster dose leads to increased antibody levels compared to a fresh 2-dose vaccine, which may suggest increased effectiveness. To compare the real-world effectiveness of a fresh (up to 60 days) booster dose with that of a fresh 2-dose vaccine, we took advantage of a quasi-experimental study that compares populations that were eligible to receive the vaccine at different times due to age-dependent policies. Specifically, we compared the confirmed infection rates in adolescents aged 12-14 (215,653 individuals) who received the 2-dose vaccine and in adolescents aged 16-18 (103,454 individuals) who received the booster dose. Our analysis shows that the confirmed infection rate was lower by a factor of 3.7 (95% CI: 2.7 to 5.2) in the booster group.

The number needed to treat adjusted for explanatory variables in regression and survival analysis: Theory and application.

The number needed to treat (NNT) is an efficacy index commonly used in randomized clinical trials. The NNT is the average number of treated patients for each undesirable patient outcome, for example, death, prevented by the treatment. We introduce a systematic theoretically-based framework to model and estimate the conditional and the harmonic mean NNT in the presence of explanatory variables, in various models with dichotomous and nondichotomous outcomes. The conditional NNT is illustrated in a series of four primary examples; logistic regression, linear regression, Kaplan-Meier estimation, and Cox regression models. Also, we establish and prove mathematically the exact relationship between the conditional and the harmonic mean NNT in the presence of explanatory variables. We introduce four different methods to calculate asymptotically-correct confidence intervals for both indices. Finally, we implemented a simulation study to provide numerical demonstrations of the aforementioned theoretical results and the four examples. Numerical analysis showed that the parametric estimators of the NNT with nonparametric bootstrap-based confidence intervals outperformed other examined combinations in most settings. An R package and a web application have been developed and made available online to calculate the conditional and the harmonic mean NNTs with their corresponding confidence intervals.

Serum folate deficiency and the risks of dementia and all-cause mortality: a national study of old age.

BACKGROUND: The association between serum folate deficiency and the risk of dementia in old age is unclear, perhaps owing to small sample sizes, the competing risk of mortality or reverse causation. OBJECTIVE: To examine the associations between serum folate deficiency and the risks of incident dementia and all-cause mortality in a large national sample of older adults. METHODS: A prospective cohort aged 60-75 years (n=27 188) without pre-existing dementia for at least 10 years, was tested for serum concentrations of folate and followed up for dementia or all-cause mortality. Serum folate deficiency was classified as present (<4.4 ng/mL), otherwise absent. HRs and 95% CIs from competing risks Cox models were fitted to quantify the associations between serum folate deficiency and the risks of dementia and all-cause mortality. To examine reverse causation, the analysis was stratified by duration of follow-up. FINDINGS: The presence compared with the absence of serum folate deficiency was associated with higher risks of dementia (HR=1.68; 95% CI 1.32 to 2.13; p<0.001) and all-cause mortality (HR=2.98; 95% CI 2.52 to 3.52; p<0.001). Evidence for reverse causation were moderate for dementia and mild for all-cause mortality. CONCLUSIONS: Serum concentrations of folate may function as a biomarker used to identify those at risk of dementia and mortality; however, reverse causation is likely. Further research is needed to examine the role of serum folate deficiency in dementia aetiology. CLINICAL IMPLICATIONS: Serum folate deficiency in older adults requires monitoring and treatment for preventative measures and/or as part of implemented therapeutic strategies.