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<title>Nested case–control study</title>

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<span id="openzim-page-title" class="mw-page-title-main"><span class="mw-page-title-main">Nested case–control study</span></span>

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<div id="mw-content-text" class="mw-body-content mw-content-ltr" lang="en" dir="ltr"><div class="mw-content-ltr mw-parser-output" lang="en" dir="ltr"><p>A <b>nested case–control (NCC) study</b> is a variation of a case–control study in which cases and controls are drawn from the population in a fully enumerated cohort.

</p><p>Usually, the exposure of interest is only measured among the cases and the selected controls. Thus the nested case–control study is more efficient than the full cohort design. The nested case–control study can be analyzed using methods for missing covariates.

</p><p>The NCC design is often used when the exposure of interest is difficult or expensive to obtain and when the outcome is rare. By utilizing data previously collected from a large cohort study, the time and cost of beginning a new case–control study is avoided. By only measuring the covariate in as many participants as necessary, the cost and effort of exposure assessment is reduced. This benefit is pronounced when the covariate of interest is biological, since assessments such as gene expression profiling are expensive, and because the quantity of blood available for such analysis is often limited, making it a valuable resource that should not be used unnecessarily.

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<div class="mw-heading mw-heading2"><h2 id="Example">Example</h2></div>

<p>As an example, of the 91,523 women in the <a href="Nurses'_Health_Study" title="Nurses' Health Study">Nurses' Health Study</a> who did not have cancer at baseline and who were followed for 14 years, 2,341 women had developed breast cancer by 1993. Several studies have used standard cohort analyses to study precursors to breast cancer, e.g. use of hormonal contraceptives,<sup id="cite_ref-pmid9051324_1-0" class="reference"><a href="#cite_note-pmid9051324-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> which is a covariate easily measured on all of the women in the cohort. However, note that in comparison to the cases, there are so many controls that each particular control contributes relatively little information to the analysis.

</p><p>If, on the other hand, one is interested in the association between <a href="Gene_expression" title="Gene expression">gene expression</a> and breast cancer incidence, it would be very expensive and possibly wasteful of precious blood specimen to assay all 89,000 women without breast cancer. In this situation, one may choose to assay all of the cases, and also, for each case, select a certain number of women to assay from the risk set of participants who have not yet failed (i.e. those who have not developed breast cancer before the particular case in question has developed breast cancer). The risk set is often restricted to those participants who are matched to the case on variables such as age, which reduces the variability of effect estimates.

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<div class="mw-heading mw-heading2"><h2 id="Efficiency_of_the_NCC_model">Efficiency of the NCC model</h2></div>

<p>Commonly 1–4 controls are selected for each case. Since the covariate is not measured for all participants, the nested case–control model is both less expensive than a full cohort analysis and more efficient than taking a simple random sample from the full cohort. However, it has been shown that with 4 controls per case and/or stratified sampling of controls, relatively little efficiency may be lost, depending on the method of estimation used.<sup id="cite_ref-Cai_2-0" class="reference"><a href="#cite_note-Cai-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-3" class="reference"><a href="#cite_note-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading2"><h2 id="Analysis_of_nested_case–control_studies">Analysis of nested case–control studies</h2></div>

<p>The analysis of a nested case–control model must take into account the way in which controls are sampled from the cohort. Failing to do so, such as by treating the cases and selected controls as the original cohort and performing a logistic regression, which is common, can result in biased estimates whose null distribution is different from what is assumed. Ways to account for the random sampling include <a href="Conditional_logistic_regression" title="Conditional logistic regression">conditional logistic regression</a>,<sup id="cite_ref-4" class="reference"><a href="#cite_note-4"><span class="cite-bracket">[</span>4<span class="cite-bracket">]</span></a></sup> and using <a href="Inverse_probability_weighting" title="Inverse probability weighting">inverse probability weighting</a> to adjust for missing covariates among those who are not selected into the study.<sup id="cite_ref-Cai_2-1" class="reference"><a href="#cite_note-Cai-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading2"><h2 id="Case–cohort_study">Case–cohort study</h2></div>

<p>A case–cohort study is a design in which cases and controls are drawn from within a prospective study. All cases who developed the outcome of interest during the follow-up are selected and compared with a random sample of the cohort. This randomly selected control sample could, by chance, include some cases. Exposure is defined prior to disease development based on data collected at baseline or on assays conducted in biological samples collected at baseline.

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<div class="mw-heading mw-heading2"><h2 id="References">References</h2></div>

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</style><cite id="CITEREFHankinson_SEColditz_GAManson_JEWillett_WC1997" class="citation journal cs1">Hankinson SE; Colditz GA; Manson JE; Willett WC; Hunter DJ; Stampfer MJ; et al. (1997). "A prospective study of oral contraceptive use and risk of breast cancer (Nurses' Health Study, United States)". <i>Cancer Causes Control</i>. <b>8</b> (1): <span class="nowrap">65–</span>72. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1023%2Fa%3A1018435205695">10.1023/a:1018435205695</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/9051324">9051324</a>. <a href="S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:24873830">24873830</a>.</cite></span>

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<li id="cite_note-Cai-2"><span class="mw-cite-backlink">^ <a href="#cite_ref-Cai_2-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-Cai_2-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text"><cite id="CITEREFCaiZheng2012" class="citation journal cs1"><a href="Tianxi_Cai" title="Tianxi Cai">Cai, Tianxi</a>; Zheng, Yingye (2012). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276269">"Evaluating prognostic accuracy of biomarkers in nested case–control studies"</a>. <i>Biostatistics</i>. <b>13</b> (1): <span class="nowrap">89–</span>100. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1093%2Fbiostatistics%2Fkxr021">10.1093/biostatistics/kxr021</a>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276269">3276269</a></span>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/21856652">21856652</a>.</cite></span>

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<li id="cite_note-3"><span class="mw-cite-backlink"><b><a href="#cite_ref-3">^</a></b></span> <span class="reference-text"><cite id="CITEREFGoldsteinZhang2009" class="citation journal cs1">Goldstein, Larry; Zhang, Haimeng (2009). "Efficiency of the maximum partial likelihood estimator for nested case control sampling". <i>Bernoulli</i>. <b>15</b> (2): <span class="nowrap">569–</span>597. <a href="ArXiv_(identifier)" class="mw-redirect" title="ArXiv (identifier)">arXiv</a>:<span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://arxiv.org/abs/0809.0445">0809.0445</a></span>. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.3150%2F08-bej162">10.3150/08-bej162</a>. <a href="JSTOR_(identifier)" class="mw-redirect" title="JSTOR (identifier)">JSTOR</a> <a rel="nofollow" class="external text" href="https://www.jstor.org/stable/20680165">20680165</a>. <a href="S2CID_(identifier)" class="mw-redirect" title="S2CID (identifier)">S2CID</a> <a rel="nofollow" class="external text" href="https://api.semanticscholar.org/CorpusID:16589954">16589954</a>.</cite></span>

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<li id="cite_note-4"><span class="mw-cite-backlink"><b><a href="#cite_ref-4">^</a></b></span> <span class="reference-text"><cite id="CITEREFBorganGoldsteinLangholz1995" class="citation journal cs1">Borgan, O.; Goldstein, L.; Langholz, B. (1995). <a rel="nofollow" class="external text" href="https://www.duo.uio.no/bitstream/10852/47861/1/1992-7.pdf">"Methods for the Analysis of Sampled Cohort Data in the Cox Proportional Hazards Model"</a> <span class="cs1-format">(PDF)</span>. <i><a href="Annals_of_Statistics" title="Annals of Statistics">Annals of Statistics</a></i>. <b>23</b> (5): <span class="nowrap">1749–</span>1778. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<span class="id-lock-free" title="Freely accessible"><a rel="nofollow" class="external text" href="https://doi.org/10.1214%2Faos%2F1176324322">10.1214/aos/1176324322</a></span>. <a href="JSTOR_(identifier)" class="mw-redirect" title="JSTOR (identifier)">JSTOR</a> <a rel="nofollow" class="external text" href="https://www.jstor.org/stable/2242544">2242544</a>.</cite></span>

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<p><cite id="CITEREFPorta2014" class="citation book cs1">Porta, Miquel (2014). <i>A Dictionary of Epidemiology</i>. Oxford: Oxford University Press.</cite>

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<div class="mw-heading mw-heading2"><h2 id="Further_reading">Further reading</h2></div>

<ul><li><cite id="CITEREFKeoghCox2014" class="citation book cs1">Keogh, Ruth H.; <a href="David_Cox_(statistician)" title="David Cox (statistician)">Cox, D. R.</a> (2014). <a rel="nofollow" class="external text" href="https://books.google.com/books?id=GdXSAgAAQBAJ&pg=PA160">"Nested case–control studies"</a>. <i>Case–Control Studies</i>. Cambridge University Press. pp. <span class="nowrap">160–</span>190. <a href="ISBN_(identifier)" class="mw-redirect" title="ISBN (identifier)">ISBN</a> <bdi>978-1-107-01956-0</bdi>.</cite></li></ul>

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</style><div id="Clinical_research_and_experimental_design505" style="font-size:114%;margin:0 4em"><a href="Clinical_research" title="Clinical research">Clinical research</a> and <a href="Design_of_experiments" title="Design of experiments">experimental design</a></div></th></tr><tr><th scope="row" class="navbox-group" style="width:1%">Overview</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Clinical_trial" title="Clinical trial">Clinical trial</a>

<ul><li><a href="Protocol_(science)" title="Protocol (science)">Trial protocols</a></li>

<li><a href="Adaptive_clinical_trial" class="mw-redirect" title="Adaptive clinical trial">Adaptive clinical trial</a></li></ul></li>

<li><a href="Academic_clinical_trials" class="mw-redirect" title="Academic clinical trials">Academic clinical trials</a></li>

<li><a href="Clinical_study_design" title="Clinical study design">Clinical study design</a></li>

<li><a href="Evidence-based_medicine" title="Evidence-based medicine">Evidence-based medicine</a></li>

<li><a href="Real_world_evidence" title="Real world evidence">Real world evidence</a></li>

<li><a href="Patient_and_public_involvement" title="Patient and public involvement">Patient and public involvement</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Scientific_control" title="Scientific control">Controlled study</a><br>(<a href="Hierarchy_of_evidence#USA" title="Hierarchy of evidence">EBM I to II-1</a>)</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Randomized_controlled_trial" title="Randomized controlled trial">Randomized controlled trial</a>

<ul><li><a href="Experiment" title="Experiment">Scientific experiment</a></li>

<li><a href="Blind_experiment" class="mw-redirect" title="Blind experiment">Blind experiment</a></li>

<li><a href="Open-label_trial" title="Open-label trial">Open-label trial</a></li></ul></li>

<li><a href="Adaptive_clinical_trial" class="mw-redirect" title="Adaptive clinical trial">Adaptive clinical trial</a>

<ul><li><a href="Platform_trial" title="Platform trial">Platform trial</a></li></ul></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Observational_study" title="Observational study">Observational study</a><br>(<a href="Hierarchy_of_evidence#USA" title="Hierarchy of evidence">EBM II-2 to II-3</a>)</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Cross-sectional_study" title="Cross-sectional study">Cross-sectional study</a> vs. <a href="Longitudinal_study" title="Longitudinal study">Longitudinal study</a>, <a href="Ecological_study" title="Ecological study">Ecological study</a></li>

<li><a href="Cohort_study" title="Cohort study">Cohort study</a>

<ul><li><a href="Retrospective_cohort_study" title="Retrospective cohort study">Retrospective</a></li>

<li><a href="Prospective_cohort_study" title="Prospective cohort study">Prospective</a></li></ul></li>

<li><a href="Case%E2%80%93control_study" title="Case–control study">Case–control study</a> ()</li>

<li><a href="Case_series" title="Case series">Case series</a></li>

<li><a href="Case_study" title="Case study">Case study</a></li>

<li><a href="Case_report" title="Case report">Case report</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Outcome_measure" title="Outcome measure">Measures</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Epidemiological_methods" class="mw-redirect" title="Epidemiological methods">Occurrence</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"><a href="Incidence_(epidemiology)" title="Incidence (epidemiology)">Incidence</a>, <a href="Cumulative_incidence" class="mw-redirect" title="Cumulative incidence">Cumulative incidence</a>, <a href="Prevalence" title="Prevalence">Prevalence</a>, <a href="Point_prevalence" class="mw-redirect" title="Point prevalence">Point prevalence</a>, <a href="Period_prevalence" class="mw-redirect" title="Period prevalence">Period prevalence</a></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Epidemiological_methods" class="mw-redirect" title="Epidemiological methods">Association</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"><a href="Risk_difference" title="Risk difference">Risk difference</a>, <a href="Number_needed_to_treat" title="Number needed to treat">Number needed to treat</a>, <a href="Number_needed_to_harm" title="Number needed to harm">Number needed to harm</a>, <a href="Risk_ratio" class="mw-redirect" title="Risk ratio">Risk ratio</a>, <a href="Relative_risk_reduction" title="Relative risk reduction">Relative risk reduction</a>, <a href="Odds_ratio" title="Odds ratio">Odds ratio</a>, <a href="Hazard_ratio" title="Hazard ratio">Hazard ratio</a></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Population_impact_measure" title="Population impact measure">Population impact</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"><a href="Attributable_fraction_among_the_exposed" title="Attributable fraction among the exposed">Attributable fraction among the exposed</a>, <a href="Attributable_fraction_for_the_population" title="Attributable fraction for the population">Attributable fraction for the population</a>, <a href="Preventable_fraction_among_the_unexposed" title="Preventable fraction among the unexposed">Preventable fraction among the unexposed</a>, <a href="Preventable_fraction_for_the_population" title="Preventable fraction for the population">Preventable fraction for the population</a></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Epidemiological_methods" class="mw-redirect" title="Epidemiological methods">Other</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"><a href="Clinical_endpoint" title="Clinical endpoint">Clinical endpoint</a>, <a href="Virulence" title="Virulence">Virulence</a>, <a href="Infectivity" title="Infectivity">Infectivity</a>, <a href="Mortality_rate" title="Mortality rate">Mortality rate</a>, <a href="Morbidity" class="mw-redirect" title="Morbidity">Morbidity</a>, <a href="Case_fatality_rate" title="Case fatality rate">Case fatality rate</a>, <a href="Specificity_and_sensitivity" class="mw-redirect" title="Specificity and sensitivity">Specificity and sensitivity</a>, <a href="Likelihood_ratios_in_diagnostic_testing" title="Likelihood ratios in diagnostic testing">Likelihood-ratios</a>, <a href="Pre-_and_post-test_probability" title="Pre- and post-test probability">Pre- and post-test probability</a></div></td></tr></tbody></table><div></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Trial/test types</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="In_vitro" title="In vitro">In vitro</a></li>

<li><a href="Animal_testing" title="Animal testing">Animal testing</a></li>

<li><a href="Animal_testing_on_non-human_primates" title="Animal testing on non-human primates">Animal testing on non-human primates</a></li>

<li><a href="First-in-man_study" class="mw-redirect" title="First-in-man study">First-in-man study</a></li>

<li><a href="Multicenter_trial" title="Multicenter trial">Multicenter trial</a></li>

<li><a href="Seeding_trial" title="Seeding trial">Seeding trial</a></li>

<li><a href="Vaccine_trial" title="Vaccine trial">Vaccine trial</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Analysis_of_clinical_trials" title="Analysis of clinical trials">Analysis of clinical trials</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Risk%E2%80%93benefit_ratio" title="Risk–benefit ratio">Risk–benefit ratio</a></li>

<li><a href="Systematic_review" title="Systematic review">Systematic review</a></li>

<li><a href="Reproducibility" title="Reproducibility">Replication</a></li>

<li><a href="Meta-analysis" title="Meta-analysis">Meta-analysis</a></li>

<li><a href="Intention-to-treat_analysis" title="Intention-to-treat analysis">Intention-to-treat analysis</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Interpretation of results</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Selection_bias" title="Selection bias">Selection bias</a></li>

<li><a href="Survivorship_bias" title="Survivorship bias">Survivorship bias</a></li>

<li><a href="Correlation_does_not_imply_causation" title="Correlation does not imply causation">Correlation does not imply causation</a></li>

<li><a href="Null_result" title="Null result">Null result</a></li>

<li><a href="Sex_as_a_biological_variable" title="Sex as a biological variable">Sex as a biological variable</a></li></ul>

</div></td></tr><tr><td class="navbox-abovebelow" colspan="2"><div>

<ul><li><b>Category</b></li>

<li><b><a href="Glossary_of_clinical_research" title="Glossary of clinical research">Glossary</a></b></li>

<li><b><a href="List_of_clinical_research_topics" class="mw-redirect" title="List of clinical research topics">List of topics</a></b></li></ul>

</div></td></tr></tbody></table></div></div><div><div class="zim-footer">

This article is issued from <a class="external text" title="Last edited on 2025-07-26" href="https://en.wikipedia.org/wiki/?title=Nested_case%E2%80%93control_study&oldid=1302538415">Wikipedia</a>. The text is available under <a class="external text" href="https://creativecommons.org/licenses/by-sa/4.0/deed.en">Creative Commons Attribution-Share Alike 4.0</a> unless otherwise noted. Additional terms may apply for the media files.

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