Fundamental method of trial sequential analysis

Sequential method has the capability to manage the overall Type I error in clinical trials and cumulative meta-analyses through the utilization of an alpha spending function, exemplified by the approach introduced by O’Brien & Fleming (1979). Based on required sample size (RSS) or required information size (RIS), sequential analysis applies the alpha spending function to allocate less significance level to early interim analyses, demanding more substantial evidence for declaring statistical significance. Critical boundaries for significance are determined by this function, becoming less stringent as more data accumulates. Sequential analysis uses these boundaries to monitor effects at each interim analysis, declaring statistical significance if the cumulative Z-score crosses them. This approach minimizes the risk of false positives in sequential analyses, where multiple interim analyses are conducted, while maintaining the ability to detect true effects.

Therefor, the essentials of sequential meta-analysis encompass various elements including study time, sample size, and cumulative Z-scores derived from cumulative meta-analysis following a temporal order. Additionally, integral to this analysis are the anticipated effects of intervention or exposure, which are either predetermined or established through prior estimates, along with their respective variances. Moreover, the formulation accounts for predefined probabilities associated with Type I error (denoted as α) and Type II error (denoted as β). Leveraging this comprehensive set of parameters, particularly the anticipated effects and their associated variances in conjunction with α and β, this methodology facilitates the computation of the RIS and the establishment of alpha-spending monitoring boundaries. By charting the information size axis, the analysis offers a comprehensive visualization of the cumulative Z-scores and the accompanying alpha-spending monitoring boundaries (Wetterslev et al., 2008; Wetterslev et al., 2009; Wetterslev et al., 2017).

Within the realm of sequential method, the concept of the RIS holds paramount significance as it serves as the cornerstone for establishing spending monitoring boundaries, necessitated by adjustments to accommodate multiple interim analyses (Wetterslev et al., 2017). Essentially, sequential methods encompass considerations pertinent to sample size determination, albeit employing an approach divergent from conventional methodologies employed in hypothesis testing or estimation. The determination of the information size, delineating the RSS, hinges crucially upon various parameters including the anticipated effect size, statistical power, significance level, and any requisite adjustments tailored for multiple testing scenarios. Conventionally, the determination of the RSS encompasses an assessment of intervention or exposure effects, their variance, as well as the predefined probabilities associated with Type I error (α) and Type II error (β). The formula governing the calculation of the RSS is as follows:

Where

α represents the predefined overall probabilities of false positive.
β represents the predefined overall probabilities of false negative.
δ refers to the assumed effect, representing either the minimal or expected meaningful effect.
σ² refers to the variance that associated with the assumed effect.

In the context of dichotomous outcomes, the parameter δ can be substituted with the effect size that a trial aims to address, denoted by μ, derived from the difference in proportions between the control and experimental groups, represented by P_control − P_experiment. Here, P_control and P_experiment signify the proportions of observed events in the control and experimental groups, respectively. The variance σ² is computed as P_average × (1 − P_average), where P_average is derived from (P_control + P_experiment)/2 (Wetterslev et al., 2017). For continuous outcomes, the RSS can be determined as follows:

Where

α represents the predefined overall probabilities of false positive.
β represents the predefined overall probabilities of false negative.
MD refers to the assumed mean difference between two groups.
SD refers to the standard deviation that associated with the assumed mean difference.

Based on the basic formula for calculating RSS, RIS in sequential method could be calculated by using assumed pooled effect and the variance that associated with the assumed pooled effect (Wetterslev et al., 2017). Thus, the formula for the calculation of the RIS for meta-analysis in fixed-effect model is as follows:

Where

α represents the predefined overall probabilities of false positive.
β represents the predefined overall probabilities of false negative.
θ refers to the assumed pooled effect, representing either the minimal or expected meaningful effect.
V_fixed refers to the variance that associated with the assumed pooled effect in fixed-effect model.

In meta-analysis employing the random-effects model, the calculation of the RIS follows a similar formula, but with a substitution of the variance associated with the assumed pooled effect by the variance specific to the random-effects model. RIS for meta-sequential analysis in random-effects model can be denoted as RIS_random. For a conservative estimation of the RIS in meta-analyses featuring heterogeneity, it is advisable to incorporate a heterogeneity correction factor (Wetterslev et al., 2008), also referred to as the Adjusted Factor (AF) in Trial Sequential Analysis (TSA) (Wetterslev et al., 2009; Wetterslev et al., 2017). Obviously, the calculation of the heterogeneity correction factor is inherently tied to the heterogeneity statistics. The I-squared statistic (denoted as I²) is particularly suited for this purpose, serving as a widely utilized measure for quantifying and assessing heterogeneity (Higgins & Thompson, 2002). I²-based AF (denoted as AF_I²) can be derived from the formula as follow:

However, I² may provide misleading estimates due to uncertainties in the sampling error could introduce bias or inaccuracies into the analysis. Alternative measures or adjustments that are less susceptible to issues related to sampling error estimation should be considered (Wetterslev et al., 2009). Diversity (denoted as D²) has been proposed as a pivotal parameter in the computation of AF for the RIS in random-effects meta-analysis (Wetterslev et al., 2009; Wetterslev et al., 2017). It is derived from the variances observed in both the random-effects model (V_random) and the fixed-effect model (V_fixed). The formula for calculating D² is as follows:

Then, the calculation of D²-based AF (denoted as AF_D²) is similar to the formula of AF_I² with replacement of I² by D². When addressing concerns regarding sampling error or bias, AF_D² offers notable advantages over AF_I² because D² operates without the prerequisite of assuming a typical sampling error (usually denoted as σ²). Besides, it accurately mirrors the relative variance expansion resultant from the between-trial variance estimate, and exhibits a propensity to diminish as the estimate decreases, even when applied to identical study sets (Wetterslev et al., 2009).

To provide a conservative estimation of the RIS for meta-analyses with heterogeneity, it is recommended to utilize an adjusted RIS. This can be achieved by multiplying RIS_random by the AF (Wetterslev et al., 2009). Subsequently, there are two the I-squared-adjusted information size (HIS) can be derived by further multiplying RIS_random by AF_I². Similarly, the diversity-adjusted information size (DIS) is obtained by calculating RIS_random multiplied by AF_D², as suggested by Wetterslev et al. (2009).