Get access

Symptom index P-value and symptom sensitivity index P-value to determine symptom association between apnea and reflux in premature infants at term


  • This publication was made possible by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.
  • Disclosures
  • Daniel Glen is affiliated to the National Institute of Mental Health, National Institute of Health but has contributed to this article in a private capacity, and the views expressed in the article do not necessarily represent the views of NIH or the United States.
  • Peter Murakami and Jeanne Nunez, MD do not have any conflicts of interest.

Address correspondence to: Dr Jeanne S. Nunez, MD, Division of Neonatology Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue Baltimore, MD 21224-2780, USA. Email:


The current method to determine temporal association (TA) between reflux and symptoms is the symptom association probability (SAP), but this method has limitations due to the constraints of binning and the violation of statistical principles of the Fisher's exact test that lead to an invalid estimation of TA. The aim of this study is to develop improved methods of computing the TA between apneic and reflux events using simulation and permutation methods and to compare these to the SAP. TA was analyzed between polysomnographic obstructive apneas and multichannel intraluminal impedance (MII) reflux events. Three new numerical methods were compared to the SAP in four former premature infants with persistent apneas at term. The experimentally found association was compared to the association observed in simulated or permuted data consistent with the lack of association beyond what is expected by chance alone. Temporal association was computed based on symptom and symptom sensitivity indices, SI and SSI, with varying window of association (WA) times from 15 to 300 s. The three new methods estimated P-values at varying WA that generally followed the same pattern of the SAP which had a more erratic pattern. The WA that gave the lowest P-value was approximately 120 s. Each of the novel methods produced P-value results consistent with each other and the SAP yet not subject to its limitations. The variation of WA gave a temporal profile of TA providing clues to its etiology. These new metrics are called Symptom Index (SIP) and Symptom Sensitivity Index (SSIP) P-values.