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Logrank test

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Hypothesis test to compare the survival distributions of two samples

Thelogrank test, orlog-rank test, is ahypothesis test to compare thesurvival distributions of two samples. It is anonparametric test and appropriate to use when the data are right skewed andcensored (technically, the censoring must be non-informative). It is widely used inclinical trials to establish the efficacy of a new treatment in comparison with a control treatment when the measurement is the time to event (such as the time from initial treatment to a heart attack). The test is sometimes called theMantel–Cox test. The logrank test can also be viewed as a time-stratifiedCochran–Mantel–Haenszel test.

The test was first proposed byNathan Mantel and was named thelogrank test byRichard andJulian Peto.[1][2][3]

Definition

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The logrank test statistic compares estimates of thehazard functions of the two groups at each observed event time. It is constructed by computing the observed and expected number of events in one of the groups at each observed event time and then adding these to obtain an overall summary across all-time points where there is an event.

Consider two groups of patients, e.g., treatment vs. control. Let1,,J{\displaystyle 1,\ldots ,J} be the distinct times of observed events in either group. LetN1,j{\displaystyle N_{1,j}} andN2,j{\displaystyle N_{2,j}} be the number of subjects "at risk" (who have not yet had an event or been censored) at the start of periodj{\displaystyle j} in the groups, respectively. LetO1,j{\displaystyle O_{1,j}} andO2,j{\displaystyle O_{2,j}} be the observed number of events in the groups at timej{\displaystyle j}. Finally, defineNj=N1,j+N2,j{\displaystyle N_{j}=N_{1,j}+N_{2,j}} andOj=O1,j+O2,j{\displaystyle O_{j}=O_{1,j}+O_{2,j}}.

Thenull hypothesis is that the two groups have identical hazard functions,H0:h1(t)=h2(t){\displaystyle H_{0}:h_{1}(t)=h_{2}(t)}. Hence, underH0{\displaystyle H_{0}}, for each groupi=1,2{\displaystyle i=1,2},Oi,j{\displaystyle O_{i,j}} follows ahypergeometric distribution with parametersNj{\displaystyle N_{j}},Ni,j{\displaystyle N_{i,j}},Oj{\displaystyle O_{j}}. This distribution has expected valueEi,j=OjNi,jNj{\displaystyle E_{i,j}=O_{j}{\frac {N_{i,j}}{N_{j}}}} and varianceVi,j=Ei,j(NjOjNj)(NjNi,jNj1){\displaystyle V_{i,j}=E_{i,j}\left({\frac {N_{j}-O_{j}}{N_{j}}}\right)\left({\frac {N_{j}-N_{i,j}}{N_{j}-1}}\right)}.

For allj=1,,J{\displaystyle j=1,\ldots ,J}, the logrank statistic comparesOi,j{\displaystyle O_{i,j}} to its expectationEi,j{\displaystyle E_{i,j}} underH0{\displaystyle H_{0}}. It is defined as

Zi=j=1J(Oi,jEi,j)j=1JVi,j d N(0,1){\displaystyle Z_{i}={\frac {\sum _{j=1}^{J}(O_{i,j}-E_{i,j})}{\sqrt {\sum _{j=1}^{J}V_{i,j}}}}\ {\xrightarrow {d}}\ {\mathcal {N}}(0,1)}      (fori=1{\displaystyle i=1} or2{\displaystyle 2})

It is easy to see that for allj{\displaystyle j},O2,jE2,j=(O1,jE1,j){\displaystyle O_{2,j}-E_{2,j}=-(O_{1,j}-E_{1,j})} andV2,j=V1,j{\displaystyle V_{2,j}=V_{1,j}}, soZ2=Z1{\displaystyle Z_{2}=-Z_{1}}.

By thecentral limit theorem, the distribution of eachZi{\displaystyle Z_{i}} converges to that of a standard normal distribution asJ{\displaystyle J} approaches infinity and therefore can be approximated by the standard normal distribution for a sufficiently largeJ{\displaystyle J}. An improved approximation can be obtained by equating this quantity to Pearson type I or II (beta) distributions with matching first four moments, as described in Appendix B of the Peto and Peto paper.[2]

Asymptotic distribution

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If the two groups have the same survival function, the logrank statistic is approximately standard normal. A one-sided levelα{\displaystyle \alpha } test will reject the null hypothesis ifZ>zα{\displaystyle Z>z_{\alpha }} wherezα{\displaystyle z_{\alpha }} is the upperα{\displaystyle \alpha } quantile of the standard normal distribution. If the hazard ratio isλ{\displaystyle \lambda }, there aren{\displaystyle n} total subjects,d{\displaystyle d} is the probability a subject in either group will eventually have an event (so thatnd{\displaystyle nd} is the expected number of events at the time of the analysis), and the proportion of subjects randomized to each group is 50%, then the logrank statistic is approximately normal with mean(logλ)nd4{\displaystyle (\log {\lambda })\,{\sqrt {\frac {n\,d}{4}}}} and variance 1.[4] For a one-sided levelα{\displaystyle \alpha } test with power1β{\displaystyle 1-\beta }, the sample size required isn=4(zα+zβ)2dlog2λ{\displaystyle n={\frac {4\,(z_{\alpha }+z_{\beta })^{2}}{d\log ^{2}{\lambda }}}}wherezα{\displaystyle z_{\alpha }} andzβ{\displaystyle z_{\beta }} are the quantiles of the standard normal distribution.

Joint distribution

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SupposeZ1{\displaystyle Z_{1}} andZ2{\displaystyle Z_{2}} are the logrank statistics at two different time points in the same study (Z1{\displaystyle Z_{1}} earlier). Again, assume the hazard functions in the two groups are proportional with hazard ratioλ{\displaystyle \lambda } andd1{\displaystyle d_{1}} andd2{\displaystyle d_{2}} are the probabilities that a subject will have an event at the two time points whered1d2{\displaystyle d_{1}\leq d_{2}}.Z1{\displaystyle Z_{1}} andZ2{\displaystyle Z_{2}} are approximately bivariate normal with meanslogλnd14{\displaystyle \log {\lambda }\,{\sqrt {\frac {n\,d_{1}}{4}}}} andlogλnd24{\displaystyle \log {\lambda }\,{\sqrt {\frac {n\,d_{2}}{4}}}} and correlationd1d2{\displaystyle {\sqrt {\frac {d_{1}}{d_{2}}}}}. Calculations involving the joint distribution are needed to correctly maintain the error rate when the data are examined multiple times within a study by aData Monitoring Committee.

Relationship to other statistics

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Test assumptions

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The logrank test is based on the same assumptions as theKaplan-Meier survival curve—namely, that censoring is unrelated to prognosis, the survival probabilities are the same for subjects recruited early and late in the study, and the events happened at the times specified. Deviations from these assumptions matter most if they are satisfied differently in the groups being compared, for example if censoring is more likely in one group than another.[5]

See also

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References

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  1. ^Mantel, Nathan (1966). "Evaluation of survival data and two new rank order statistics arising in its consideration".Cancer Chemotherapy Reports.50 (3):163–70.PMID 5910392.
  2. ^abPeto, Richard; Peto, Julian (1972). "Asymptotically Efficient Rank Invariant Test Procedures".Journal of the Royal Statistical Society, Series A.135 (2). Blackwell Publishing:185–207.doi:10.2307/2344317.hdl:10338.dmlcz/103602.JSTOR 2344317.
  3. ^Harrington, David (2005). "Linear Rank Tests in Survival Analysis".Encyclopedia of Biostatistics. Wiley Interscience.doi:10.1002/0470011815.b2a11047.ISBN 047084907X.
  4. ^Schoenfeld, D (1981). "The asymptotic properties of nonparametric tests for comparing survival distributions".Biometrika.68 (1):316–319.doi:10.1093/biomet/68.1.316.JSTOR 2335833.
  5. ^Bland, J. M.;Altman, D. G. (2004)."The logrank test".BMJ.328 (7447): 1073.doi:10.1136/bmj.328.7447.1073.PMC 403858.PMID 15117797.
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