The reliability and integrity of overall survival data based on follow-up records only and potential solutions to the challenges

Summary Overall survival (OS) is considered the standard clinical endpoint to support effectiveness claims in new drug applications globally, particularly for lethal conditions such as cancer. However, the source and reliability of OS in the setting of clinical trials have seldom been doubted and discussed. This study first raised the common issue that data integrity and reliability are doubtful when we collect OS information or other time-to-event endpoints based solely on simple follow-up records by investigators without supporting material, especially since the 2019 COVID-19 pandemic. Then, two rounds of discussions with 30 Chinese experts were held and 12 potential source scenarios of three methods for obtaining the time of death of participants, including death certificate, death record and follow-up record, were sorted out and analysed. With a comprehensive assessment of the 12 scenarios by legitimacy, data reliability, data acquisition efficiency, difficulty of data acquisition, and coverage of participants, both short-term and long-term recommended sources, overall strategies and detailed measures for improving the integrity and reliability of death date are presented. In the short term, we suggest integrated sources such as public security systems made available to drug inspection centres appropriately as soon as possible to strengthen supervision. Death certificates provided by participants’ family members and detailed standard follow-up records are recommended to investigators as the two channels of mutual compensation, and the acquisition of supporting materials is encouraged as long as it is not prohibited legally. Moreover, we expect that the sharing of electronic medical records and the legal disclosure of death records in established health registries can be realized with the joint efforts of the whole industry in the long-term. The above proposed solutions are mainly based on the context of China and can also provide reference for other countries in the world.

The roles of meteorological variables, demographic factors, and policy response measures in the variation of COVID-19 daily cases: Evidence from different climate zones (preprint)

It is widely considered that weather conditions affect the spread of COVID-19, but to date, the collective influence of demographic factors and government policy response measures have hardly been considered. The objective of this study is to utilize a machine learning method to assess the corresponding roles of meteorological variables, demographic factors, and government response measures in daily new cases of COVID-19 among multiple climate zones at city/county level. The overall model showed good performance with a validated R2 of 0.86, as satisfactory as individual climate zone models. Population density ranked the most important factor, followed by meteorological variables and response measures. Ultraviolet radiation and temperature dominated among meteorological factors, but the association with daily new cases seemed to be inconsistent among different climate zones. Implementing stricter response measures could help effectively contain the spread of COVID-19, but did so with a lagged effect, and the typical lockdown measures might not be applicable to all climate conditions. This study preliminarily analyzed the roles of certain factors in the transmission of COVID-19, and provided practical evidence for developing an early health warning system of global pandemics by leveraging big data technology and multiple sourced data fusion.

Insights into the practical effectiveness of RT-PCR testing for SARS-CoV-2 from serologic data, a cohort study (preprint)

Background: Virologic detection of SARS-CoV-2 through Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) has limitations for surveillance. Serologic tests can be an important complementary approach. Objective: Assess the practical performance of RT-PCR based surveillance protocols, and the extent of undetected SARS-CoV-2 transmission in Shenzhen, China. Design: Cohort study nested in a public health response. Setting: Shenzhen, China; January-May 2020. Participants: 880 PCR-negative close-contacts of confirmed COVID-19 cases and 400 residents without known exposure (main analysis). Fifty-seven PCR-positive case contacts (timing analysis). Measurements: Virological testing by RT-PCR. Measurement of anti-SARS-CoV-2 antibodies in PCR-negative contacts 2-15 weeks after initial testing using total Ab ELISA. Rates of undetected infection, performance of RT-PCR over the course of infection, and characteristics of seropositive but PCR-negative individuals were assessed. Results: The adjusted seropositivity rate for total Ab among 880 PCR-negative close-contacts was 4.1% (95%CI, 2.9% to 5.7%), significantly higher than among residents without known exposure to cases (0.0%, 95%CI, 0.0% to 1.0%). PCR-positive cases were 8.0 times (RR; 95% CI, 5.3 to 12.7) more likely to report symptoms than the PCR-negative individuals who were seropositive, but otherwise similar. RT-PCR missed 36% (95%CI, 28% to 44%) of infected close-contacts, and false negative rates appear to be highly dependent on stage of infection. Limitations: No serological data were available on PCR-positive cases. Sample size was limited, and only 20% of PCR-negative contacts met inclusion criteria. Conclusion: Even rigorous RT-PCR testing protocols may miss a significant proportion of infections, perhaps in part due to difficulties timing testing of asymptomatics for optimal sensitivity. Surveillance and control protocols relying on RT-PCR were, nevertheless, able to contain community spread in Shenzhen.

Household transmission of COVID-19, Shenzhen, January-February 2020 (preprint)

Coronavirus disease 2019 has led to more than three million cases globally. Since the first family cluster of COVID-19 cases identified in Shenzhen in early January, most of the local transmission occurred within household contacts. Identifying the factors associated with household transmission is of great importance to guide preventive measures.

Evolving Epidemiology and Effect of Non-pharmaceutical Interventions on the Epidemic of Coronavirus Disease 2019 in Shenzhen, China (preprint)

Previous studies have demonstrated the characteristics of patients with 2019 novel coronavirus disease (COVID-19). However, the effect of non-pharmaceutical interventions on the epidemic in Shenzhen, China remains unknown. Individual data of 417 cases were extracted from the epidemiological investigations and the National Infectious Disease Information System between January 1, 2020 and February 29, 2020. On the basis of important interventions, the epidemic was divided into four periods (January 1-15, January 16-22, January 23-February 5 and after February 6). We used a susceptible-exposed-infectious-asymptomatic-recovered model to evaluate the effect of interventions. Results suggested that about 53.7% were imported from Wuhan. The median age was 47 years and 52.8% were women. Severity risk increased with age and associated with male and co-existing disorders. The attack rate peaked in the third period and drastically decreased afterwards across sex, age groups and geographic regions. Children younger than 5 years showed a higher attack rate than those aged of 6~19. The effective reproductive number decreased from 1.44 to 0.05 after the highest level emergency response since January 23. Overall, the non-pharmaceutical interventions have effectively mitigated the COVID-19 outbreak in Shenzhen, China. These findings may facilitate the introduction of public health policies in other countries and regions.

Epidemiological and clinical characteristics of COVID-19 in Shenzhen, the largest migrant city of China (preprint)

We conducted a retrospective study among 417 confirmed COVID-19 cases from Jan 1 to Feb 28, 2020 in Shenzhen, the largest migrant city of China, to identify the epidemiological and clinical features in settings of high population mobility. We estimated the median incubation time to be 5.0 days. 342 (82.0%) cases were imported, 161 (38.6%) cases were identified by surveillance, and 247 (59.2%) cases were reported from cluster events. The main symptoms on admission were fever and dry cough. Most patients (91.4%) had mild or moderate illnesses. Age of 50 years or older, breathing problems, diarrhea, and longer time between the first medical visit and admission were associated with higher level of clinical severity. Surveillance-identified cases were much less likely to progress to severe illness. Although the COVID-19 epidemic has been contained in Shenzhen, close monitoring and risk assessments are imperative for prevention and control of COVID-19 in future.

Epidemiology and Transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts (preprint)

Background Rapid spread of SARS-CoV-2 in Wuhan prompted heightened surveillance in Shenzhen and elsewhere in China. The resulting data provide a rare opportunity to measure key metrics of disease course, transmission, and the impact of control. Methods The Shenzhen CDC identified 391 SARS-CoV-2 cases from January 14 to February 12, 2020 and 1286 close contacts. We compare cases identified through symptomatic surveillance and contact tracing, and estimate the time from symptom onset to confirmation, isolation, and hospitalization. We estimate metrics of disease transmission and analyze factors influencing transmission risk. Findings Cases were older than the general population (mean age 45) and balanced between males (187) and females (204). Ninety-one percent had mild or moderate clinical severity at initial assessment. Three have died, 225 have recovered (median time to recovery is 21 days). Cases were isolated on average 4.6 days after developing symptoms; contact tracing reduced this by 1.9 days. Household contacts and those travelling with a case where at higher risk of infection (ORs 6 and 7) than other close contacts. The household secondary attack rate was 15%, and children were as likely to be infected as adults. The observed reproductive number was 0.4, with a mean serial interval of 6.3 days. Interpretation Our data on cases as well as their infected and uninfected close contacts provide key insights into SARS-CoV-2 epidemiology. This work shows that heightened surveillance and isolation, particularly contact tracing, reduces the time cases are infectious in the community, thereby reducing R. Its overall impact, however, is uncertain and highly dependent on the number of asymptomatic cases. We further show that children are at similar risk of infection as the general population, though less likely to have severe symptoms; hence should be considered in analyses of transmission and control.