Syndromes are defined with signs or symptoms that occur together and represent conditions. We use a data-driven approach to identify the deadliest and most death-averse frailty syndromes based on frailty symptoms. A list of 72 frailty symptoms was retrieved based on three frailty indices. We used data from the Health and Retirement Study (HRS), a longitudinal study following Americans aged 50 years and over. Principal component (PC)-based syndromes were derived based on a principal component analysis of the symptoms. Equal-weight 4-item syndromes were the sum of any four symptoms. Discrete-time survival analysis was conducted to compare the predictive power of derived syndromes on mortality. Deadly syndromes were those that significantly predicted mortality with positive regression coefficients and death-averse ones with negative coefficients. There were 2,797 of 5,041 PCbased and 964,774 of 971,635 equal-weight 4-item syndromes significantly associated with mortality. The input symptoms with the largest regression coefficients could be summed with three other input variables with small regression coefficients to constitute the leading deadliest and the most deathaverse 4-item equal-weight syndromes. In addition to chance alone, input symptoms' variances and the regression coefficients or p values regarding mortality prediction are associated with the identification of significant syndromes.Conceptually, frailty syndromes are similar to composite measures or indices that are sums of multiple input variables with equal or unequal weights 20 . Given how differently they are measured and the distinctive theories that inspired them, it is surprising that most frailty syndromes are significantly associated with major health outcomes, especially mortality. One reason is that significant health outcomes may be more likely to be published 21 . Alternatively, there are numerous candidate syndromes to screen, test, and publish. Recent findings in index mining suggest that syndromes can be searched systematically using large data sets and pre-specified rules 20 . For example, there are 72 frailty symptoms identified to form frailty syndromes in the Health and Retirement Study (HRS), and a large number of possible combinations are available 20,22 . Facing this large number of candidate syndromes, there are no well-established criteria to select clinically meaningful syndromes regardless of its statistical significance 18 . The underlying causes associated with new statistically significant frailty syndromes with important outcomes have not been identified. It is necessary to identify the factors contributing to statistical significances of frailty syndromes before assessing the importance of statistical significances in frailty syndromes. Then, a set of criteria for the selection of clinical meaningful syndromes could be developed. This study aims to identify the factors related to the statistical significances of newly generated syndromes, taking frailty syndromes as an example. The characteristics of the newly identified f...