Ethics
The study was approved by an Institutional Review Board (IRB) at Sheba Medical Center. Helsinki Approval Number: SMC-8228-21. The people included in this study were tested free of charge as part of the Israeli testing and surveillance program. Patient consent was waived as this is a retrospective analysis using data collected as part of the national testing and surveillance program. The researchers did not have access to the anonymized information.
Construction of data sets
We used a national database of Ct values of positive cases. Samples were collected between June 15, 2021, and January 29, 2022. SAS and Python were used for data retrieval, and R (version 4.0.3) and R Studio (version 1.4.1103) were used for analysis. The data set contained more than four million records of positive PCR tests with Ct values. Records contained Ct measurements for the N, E, Orf1ab, or S genes. Results are presented for N and E, and four different laboratories, two of which are Israel Health Maintenance Organization lead laboratories, which together represent ~40% of the Israeli population, and the other two are testing laboratories for the Israeli Ministry of Health. CT values< 10 or >40 units were removed from the data set, as those values are likely the result of read errors. A negligible number of such samples were identified and removed from all four laboratories, N&E final data set (9 records).
Multiple Ct measurements for the same individual and gene may belong to the same or a different infection event. Sequences of Ct measurements within a single 90-day interval were defined as belonging to the same infection events. For each of these sequences, only the first (oldest) Ct value was taken. Multiple infection events for a single individual were included if the time difference between the last measurement of the first sequence and the first measurement of the second sequence was at least 90 days. For the second infection, the patient’s status was defined as ‘Recovered’.
Initially PCR and Ct values of more than 460,000 were collected. Using encrypted identity numbers, we merge Ct data with demographic information and vaccination data to determine the patient’s age, gender, and vaccination status. The combined data contained both the Ct date and the PCR sampling date. For the Ct measurements included in this study, the number of days between these two dates was a maximum of one day. Since the PCR date is the actual sampling date, these dates were used for the analyses. Overall, our analyses, performed on samples from four laboratories and for the vaccination statuses listed below, contained 327,659 individuals, 315,111 Ct measurements for the N gene, and 228,125 measurements for the E gene.
Vaccination statuses were determined for each patient and infection event, based on the PCR laboratory date. Individuals who were infected between the first and second doses were excluded from the analysis.
The following definitions were used to group individuals (Figs. 1 and 2):
Not vaccinated: Until the first dose.
2-dose 10-39: From 10 days after the second dose to 39 days after the second dose.
2 doses 40-69: From 40 days after the second dose to 69 days after the second dose.
2 doses 70+: From 70 days after the second dose, until the third dose
3 doses 10-39: From 10 days after the third dose to 39 days after the third dose.
3 doses 40-69: From 40 days after the third dose to 69 days after the third dose.
3 doses 70+: From 70 days after the third dose, until the fourth dose
4-dose 10+: From 10 days after the fourth dose.
Recovered: Individuals who had a previous infection event with a positive PCR test at least 90 days before the current infection, and who have not received a vaccination dose between the two events.
Recovered+Vaccine: Individuals who had a prior infection event with a positive PCR test at least 90 days prior to the current infection, who received a single dose after the first infection event and no later than 10 days prior to the second infection event. infection. Results for this group are presented in Supplementary Information only.
We split the follow-up study into two separate periods, each dominated by a different variant:
Delta time period: June 15 to December 1, 2021 (>90% of cases identified as Delta, see ref. 21).
Omicron time period: December 28, 2021–January 29, 2022 (>90% of cases identified as Omicron, see ref. 21).
These periods are also in agreement with the first documented case of Omicron infection in Israel (see Supplementary Fig. 1).
To account for temporal effects in our regression analyses, we divided the Delta and Omicron time periods into 7-day time intervals (bins), using PCR dates to classify the Ct measurements. Age groups were defined as 0 to 11, 12 to 15, 16 to 39, 40 to 59, and 60 years or older. Due to national policy, people aged 0-11 years were not vaccinated until relatively late and were therefore excluded from the main analysis. However, ages 5 to 11 years were included in parts of the sensitivity analysis presented in Supplementary Note 1 (see Supplementary Table 5).
For the ‘Recovered’ decline analysis (Fig. 3), we divided the time between the first and second infection into 60-day (2-month) intervals. Intervals for which the number of samples was <50 were merged with the adjacent interval.
statistic analysis
The main tools for evaluating the effect of different factors on Ct values are linear and quantile regressions. When examining different cohorts, we used cohort, age category, gender, and categorized calendar date as explanatory variables. Daily Ct values may have been sampled from infected persons at different stages of infection (ie, time since infection). Therefore, we also examined the median and a lower quartile of Ct values, controlling for variability of age of infection (see Supplementary Tables 2 and 3). To calculate the error bars in Figs. 1-3, as well as Figs. complementary. 2–4, we use the estimated cohort coefficients, while setting all other coefficients to their mean values (as in the predictor effect plots22). We then calculated percentiles (0.025, 0.975) to obtain confidence intervals through the multivariate normal distribution.
Summary of reports
More information on the research design is available in the Nature Research Reports Summary linked to this article.
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