The clinical progress of patients hospitalized due to COVID-19 is often associated with severe pneumonia which may require intensive care, invasive ventilation, or extracorporeal membrane oxygenation ...(ECMO). The length of intensive care and the duration of these supportive therapies are clinically relevant outcomes. From the statistical perspective, these quantities are challenging to estimate due to episodes being time-dependent and potentially multiple, as well as being determined by the competing, terminal events of discharge alive and death.
We used multistate models to study COVID-19 patients' time-dependent progress and provide a statistical framework to estimate hazard rates and transition probabilities. These estimates can then be used to quantify average sojourn times of clinically important states such as intensive care and invasive ventilation. We have made two real data sets of COVID-19 patients (n = 24* and n = 53**) and the corresponding statistical code publically available.
The expected lengths of intensive care unit (ICU) stay at day 28 for the two cohorts were 15.05* and 19.62** days, while expected durations of mechanical ventilation were 7.97* and 9.85** days. Predicted mortality stood at 51%* and 15%**. Patients mechanically ventilated at the start of the example studies had a longer expected duration of ventilation (12.25*, 14.57** days) compared to patients non-ventilated (4.34*, 1.41** days) after 28 days. Furthermore, initially ventilated patients had a higher risk of death (54%* and 20%** vs. 48%* and 6%**) after 4 weeks. These results are further illustrated in stacked probability plots for the two groups from time zero, as well as for the entire cohort which depicts the predicted proportions of the patients in each state over follow-up.
The multistate approach gives important insights into the progress of COVID-19 patients in terms of ventilation duration, length of ICU stay, and mortality. In addition to avoiding frequent pitfalls in survival analysis, the methodology enables active cases to be analyzed by allowing for censoring. The stacked probability plots provide extensive information in a concise manner that can be easily conveyed to decision makers regarding healthcare capacities. Furthermore, clear comparisons can be made among different baseline characteristics.
Real-world observational data are an important source of evidence on the treatment effectiveness for patients hospitalized with coronavirus disease 2019 (COVID-19). However, observational studies ...evaluating treatment effectiveness based on longitudinal data are often prone to methodological biases such as immortal time bias, confounding bias, and competing risks.
For exemplary target trial emulation, we used a cohort of patients hospitalized with COVID-19 (n = 501) in a single centre. We described the methodology for evaluating the effectiveness of a single-dose treatment, emulated a trial using real-world data, and drafted a hypothetical study protocol describing the main components. To avoid immortal time and time-fixed confounding biases, we applied the clone-censor-weight technique. We set a 5-day grace period as a period of time when treatment could be initiated. We used the inverse probability of censoring weights to account for the selection bias introduced by artificial censoring. To estimate the treatment effects, we took the multi-state model approach. We considered a multi-state model with five states. The primary endpoint was defined as clinical severity status, assessed by a 5-point ordinal scale on day 30. Differences between the treatment group and standard of care treatment group were calculated using a proportional odds model and shown as odds ratios. Additionally, the weighted cause-specific hazards and transition probabilities for each treatment arm were presented.
Our study demonstrates that trial emulation with a multi-state model analysis is a suitable approach to address observational data limitations, evaluate treatment effects on clinically heterogeneous in-hospital death and discharge alive endpoints, and consider the intermediate state of admission to ICU. The multi-state model analysis allows us to summarize results using stacked probability plots that make it easier to interpret results.
Extending the emulated target trial approach to multi-state model analysis complements treatment effectiveness analysis by gaining information on competing events. Combining two methodologies offers an option to address immortal time bias, confounding bias, and competing risk events. This methodological approach can provide additional insight for decision-making, particularly when data from randomized controlled trials (RCTs) are unavailable.
Polyether ether ketone (PEEK) has been introduced into implant dentistry as a viable alternative to current implant abutment materials. However, data on its physico-mechanical properties are still ...scarce. The present study sought to shed light on this topic utilizing an ex vivo chewing simulator model. A total of 48 titanium two-piece implants were allocated into three groups (n = 16 per group): (1) implants with PEEK abutments and an internal butt-joint connection (PBJ), (2) implants with PEEK abutments and an internal conical implant–abutment connection (PC), and (3) implants with zirconia abutments and an internal butt-joint connection (ZA). All abutments were restored with a non-precious metal alloy crown mimicking the upper right central incisor. A dynamic chewing simulation of half (n = 8) of the specimens per group was performed with 5 × 106 cycles and a load of 49 N at a frequency of 1.7 Hz with thermocycling between 5 and 55 °C. The other eight specimens served as unloaded controls. Surface roughness, implant–abutment connection microgaps (IACMs), and the titanium base–abutment interface microgaps (TAIMs) in the loaded groups were evaluated. Finally, a quasi-static loading test was performed in a universal testing machine with all samples to evaluate fracture resistance. Overall, 23 samples survived the artificial chewing process. One abutment screw fracture was observed in the PC group. The ZA group showed higher surface roughness values than PEEK abutments. Furthermore, ZA revealed lower TAIM values compared to PEEK abutments. Similarly, ZA was associated with lower IACM values compared to PBJ. Fracture loads/bending moments were 1018 N/704 N cm for PBJ, 966 N/676 N cm for PC, and 738 N/508 N cm for ZA, with no significant differences compared to the unloaded references. Artificial loading did not significantly affect fracture resistance of the examined materials. PEEK abutments were associated with better load-bearing properties than zirconia abutments, although they showed higher microgap values. PEEK abutments could, therefore, be feasible alternatives to zirconia abutments based on the present ex vivo findings resembling 20 years of clinical service.
Objectives Many studies have attempted to determine the disease severity and patterns of COVID-19. However, at the beginning of the pandemic, the complex patients’ trajectories were only ...descriptively reported, and many analyses were worryingly prone to time-dependent-, selection-, and competing risk biases. Multi-state models avoid these biases by jointly analysing multiple clinical outcomes while taking into account their time dependency, including current cases, and modelling competing events. This paper uses a publicly available data set from the first wave in Israel as an example to demonstrate the benefits of analysing hospital data via multi-state methodology. Methods We compared the outcome of the data analysis using multi-state models with the outcome obtained when various forms of bias are ignored. Furthermore, we used Cox regression to model the transitions among the states in a multi-state model. This allowed for the comparison of the covariates’ influence on transition rates between the two states. Lastly, we calculated expected lengths of stay and state probabilities based on the multi-state model and visualised it using stacked probability plots. Results Compared to standard methods, multi-state models avoid many biases in the analysis of real-time disease developments. The utility of multi-state models is further highlighted through the use of stacked probability plots, which visualise the results. In addition, by stratification of disease patterns by subgroups and visualisation of the distribution of possible outcomes, these models bring the data into an interpretable form. Conclusion To accurately guide the provision of medical resources, this paper recommends the real-time collection of hospital data and its analysis using multi-state models, as this method eliminates many potential biases. By applying multi-state models to real-time data, the gained knowledge allows rapid detection of altered disease courses when new variants arise, which is essential when informing medical and political decision-makers as well as the general population.
By definition, in-hospital patient data are restricted to the time between hospital admission and discharge (alive or dead). For hospitalised cases of COVID-19, a number of events during ...hospitalization are of interest regarding the influence of risk factors on the likelihood of experiencing these events. The same is true for predicting times from hospital admission of COVID-19 patients to intensive care or from start of ventilation (invasive or non-invasive) to extubation. This logical restriction of the data to the period of hospitalisation is associated with a substantial risk that inappropriate methods are used for analysis. Here, we briefly discuss the most common types of bias which can occur when analysing in-hospital COVID-19 data. Keywords: competing risk bias, immortal-time bias, competing events, time-dependent bias, time-varying exposure, time-to-event analysis
The success rate of dental implants depends on primary and secondary stability. We investigate predictive factors for future risk stratification models. We retrospectively analyze 272 patients with a ...total of 582 implants. Implant stability is measured with resonance frequency analysis and evaluated based on the implant stability quotient (ISQ). A linear regression model with regression coefficients (reg. coeff.) and its 95% confidence interval (95% CI) is applied to assess predictive factors for implant stability. Implant diameter (reg. coeff.: 3.28; 95% CI: 1.89–4.66, p < 0.001), implant length (reg. coeff.: 0.67, 95% CI: 0.26–1.08, p < 0.001), and implant localization (maxillary vs. mandibular, reg. coeff.: −7.45, 95% CI: −8.70–(−6.20), p < 0.001) are significant prognostic factors for primary implant stability. An increase in ISQ between insertion and exposure is significantly correlated with healing time (reg. coeff.: 0.11, 95% CI: 0.04–0.19). Patients with maxillary implants have lower ISQ at insertion but show a higher increase in ISQ after insertion than patients with mandibular implants. We observe positive associations between primary implant stability and implant diameter, implant length, and localization (mandibular vs. maxillary). An increase in implant stability between insertion and exposure is significantly correlated with healing time and is higher for maxillary implants. These predictive factors should be further evaluated in prospective cohort studies to develop future preoperative risk-stratification models.
Multistate methodology proves effective in analyzing hospitalized coronavirus disease 2019 (COVID-19) patients with emerging variants in real time. An analysis of 2,548 admissions in Freiburg, ...Germany, showed reduced severity over time in terms of shorter hospital stays and higher discharge rates when comparing more recent phases with earlier phases of the pandemic.
This study aims to discuss and assess the impact of three prevalent methodological biases: competing risks, immortal-time bias, and confounding bias in real-world observational studies evaluating ...treatment effectiveness. We use a demonstrative observational data example of COVID-19 patients to assess the impact of these biases and propose potential solutions.
We describe competing risks, immortal-time bias, and time-fixed confounding bias by evaluating treatment effectiveness in hospitalized patients with COVID-19. For our demonstrative analysis, we use observational data from the registry of patients with COVID-19 who were admitted to the Bellvitge University Hospital in Spain from March 2020 to February 2021 and met our predefined inclusion criteria. We compare estimates of a single-dose, time-dependent treatment with the standard of care. We analyze the treatment effectiveness using common statistical approaches, either by ignoring or only partially accounting for the methodological biases. To address these challenges, we emulate a target trial through the clone-censor-weight approach.
Overlooking competing risk bias and employing the naïve Kaplan-Meier estimator led to increased in-hospital death probabilities in patients with COVID-19. Specifically, in the treatment effectiveness analysis, the Kaplan-Meier estimator resulted in an in-hospital mortality of 45.6% for treated patients and 59.0% for untreated patients. In contrast, employing an emulated trial framework with the weighted Aalen-Johansen estimator, we observed that in-hospital death probabilities were reduced to 27.9% in the "X"-treated arm and 40.1% in the non-"X"-treated arm. Immortal-time bias led to an underestimated hazard ratio of treatment.
Overlooking competing risks, immortal-time bias, and confounding bias leads to shifted estimates of treatment effects. Applying the naïve Kaplan-Meier method resulted in the most biased results and overestimated probabilities for the primary outcome in analyses of hospital data from COVID-19 patients. This overestimation could mislead clinical decision-making. Both immortal-time bias and confounding bias must be addressed in assessments of treatment effectiveness. The trial emulation framework offers a potential solution to address all three methodological biases.
Methodological biases are common in observational studies evaluating treatment effectiveness. The objective of this study is to emulate a target trial in a competing risks setting using ...hospital-based observational data. We extend established methodology accounting for immortal time bias and time-fixed confounding biases to a setting where no survival information beyond hospital discharge is available: a condition common to coronavirus disease 2019 (COVID-19) research data. This exemplary study includes a cohort of 618 hospitalized patients with COVID-19. We describe methodological opportunities and challenges that cannot be overcome applying traditional statistical methods. We demonstrate the practical implementation of this trial emulation approach via clone-censor-weight techniques. We undertake a competing risk analysis, reporting the cause-specific cumulative hazards and cumulative incidence probabilities. Our analysis demonstrates that a target trial emulation framework can be extended to account for competing risks in COVID-19 hospital studies. In our analysis, we avoid immortal time bias, time-fixed confounding bias, and competing risks bias simultaneously. Choosing the length of the grace period is justified from a clinical perspective and has an important advantage in ensuring reliable results. This extended trial emulation with the competing risk analysis enables an unbiased estimation of treatment effects, along with the ability to interpret the effectiveness of treatment on all clinically important outcomes.
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