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Table 3 Potential drivers of heterogeneity of intervention effects for different types of clinical preventive services

From: An approach to addressing subpopulation considerations in systematic reviews: the experience of reviewers supporting the U.S. Preventive Services Task Force

  Potential drivers of heterogeneity of intervention effects
Screening Baseline risk Vulnerability/risk of harms Variable responsiveness to preventive intervention Specific primary and patient-important outcomes
A. When might screening for disease risk factors result in differing net benefits for subpopulations defined by agea, race-ethnicity, sex, or other targeting factors?
Screening test for risk factors Does [the targeting factor] modify the prognostic significance of risk factors or change their prevalence (e.g., does family history carry the same relative risk in older individuals as in younger)?
Does baseline risk for the disease outcome of interest directly vary by [the targeting factor] (e.g., risk of hypertension increases with age)?
Does screening involve invasive, complicated screening tests, and [the targeting factor] that might influence risk of screening harms or willingness to be screened? Do risk factors for the disease outcome of interest for this screening test vary by differences in [the targeting factor]?
Does presence of the [targeting factor] change approaches to risk factor detection (e.g., fat redistribution with age)?
Would patient-important outcomes or values about this test differ substantially in the subpopulation defined by [the targeting factor]?
Risk factor modification Does [the targeting factor] modify the relative benefits associated with risk factor reduction (e.g., is the same degree of weight reduction in men and women associated with the same health benefits)? Does [the targeting factor] increase the vulnerability to harms from risk factor modification (e.g., caloric restriction may induce malnutrition)? Does [the targeting factor] modify the responsiveness to interventions for risk factor reduction (e.g., caloric restriction may not induce weight loss due to lower resting metabolism with older age)? Would values about this intervention or about the patient-important outcomes resulting from this risk factor intervention differ substantially in the subpopulation defined by [the targeting factor]?
B. When might screening for diminished function result in differing net benefits for subpopulations defined by agea, race-ethnicity, sex, or other targeting factors?
Screening test for reduced function Does risk of reduced function vary substantially by [the targeting factor]? Does screening involve invasive, complicated screening tests, and [the targeting factor] that might influence risk of screening harms or willingness to be screened? Does screening for reduced function vary in effectiveness or by optimal approach, depending on [the targeting factor] (e.g., is thyroid stimulating hormone equally effective in screening for hypothyroidism in all subpopulations)? Would patient-important outcomes or values about this test differ substantially in the subpopulation defined by [the targeting factor]?
Usual treatment to restore function or ameliorate dysfunction Does risk of functional impairment without treatment vary by [the targeting factor] (e.g., different natural history)? Do potential harms of usual treatment increase due to vulnerabilities associated with [the targeting factor] (e.g., greater falls with vision correction in older adults)? Is there variable responsiveness to interventions to improved function among those defined by [the targeting factor] that would further support the value of early intervention (e.g., visual correction also affecting cognitive development in young children)? Would values about this functional intervention or about the patient-important outcomes resulting from this treatment to restore function differ substantially in the subpopulation defined by [the targeting factor]?
C. When might screening for potentially fatal or disabling conditions result in differing net benefits for subpopulations defined by agea, race-ethnicity, sex, or other targeting factors?
Screening test for fatal or disabling conditions Does risk of disease vary substantially by [the targeting factor]?
Does natural history vary substantially by [the targeting factor]?
Does screening involve invasive, complicated screening tests that might influence risk of screening harms or willingness to be screened in those with [the targeting factor]?
Does risk of overdiagnosis vary by [the targeting factor]?
Does screening for potentially fatal or disabling conditions vary in effectiveness or by optimal approach, depending on [the targeting factor]? Would patient-important outcomes or values about this test differ substantially in the subpopulation defined by [the targeting factor]?
Is there heterogeneity in the components of a composite outcome by [the targeting factor]?
Treatment of screen-detected disease Does screen-detected disease generally have different prognosis by [the targeting factor]? How do treatments with potential harms, med-med interactions, or comorbidity interactions affect vulnerability/risk of harms by [the targeting factor]? Is there variable responsiveness to preventive intervention if disease detection differs by [the targeting factor]? Would values about this disease treatment or about the patient-important outcomes resulting from this disease treatment differ substantially in the subpopulation defined by [the targeting factor]?
Chemoprevention Potential drivers of heterogeneity of intervention effects
Variable responsiveness to preventive intervention Vulnerability/risk of harms Variable responsiveness to preventive intervention Specific primary and patient-important outcomes
D. When might chronic or acute disease chemopreventive interventions result in differing net benefits for subpopulations defined by agea, race-ethnicity, sex, or other targeting factors?
Chemoprevention of chronic disease Identify candidates for chemopreventive medication Does [the targeting factor] affect baseline risk for one or more outcomes of interest and help define candidates for chemoprevention (e.g., age and risk of gastrointestinal bleeding with aspirin use)?
Is [the targeting factor] part of formal risk assessment tools to identify medication candidates?
Does [the targeting factor] interact with other factors (e.g., medical history, comorbidities, cotreatments) to modify the eligibility for chemoprevention? Do chemopreventive medications require certain supports and systems that are variously available to subpopulations defined by [the targeting factor] in order to be effective? Does the disutility associated with the requirements for chemoprevention vary by [the targeting factor]?
Are there other barriers or facilitators that vary by [the targeting factor]?
Deliver chemopreventive medication Is [the targeting factor] an independent risk factor for the outcomes to be prevented, thereby increasing potential absolute benefit? Does [the targeting factor] directly increase the risk of chemoprevention-related adverse effects, or indirectly, through a greater likelihood of treatment risk modifiers, such as comorbidities, or cotreatments? Is [the targeting factor] associated with loss of/difference in responsiveness to mechanisms of prevention?
Is [the targeting factor] associated with important differences in compliance needed for benefit (e.g., dementia)?
Would patient-important outcomes or values about chemopreventive medications differ substantially in the subpopulation defined by [the targeting factor]?
Acute disease chemoprevention Identify candidates for chemopreventive medication Is there a higher baseline risk of infectious disease diagnosis or sequelae [the targeting factor]? Does [the targeting factor] interact with other factors (e.g., medical history, comorbidities, cotreatments) to modify the eligibility for chemoprevention? Do chemopreventive medications require certain supports and systems that vary in groups defined by the targeting factor] in order to be effective? Are there barriers or facilitators for taking chemopreventive medication that vary by [the targeting factor]?
Deliver chemopreventive medication Is there a larger absolute benefit by [the targeting factor] due to higher risk of disease-related outcomes? Does risk of harms with the chemopreventive medication vary in those defined by [the targeting factor]? Is [the targeting factor] associated with loss of/difference in responsiveness to mechanisms of prevention?
Is [the targeting factor] associated with important differences in compliance needed for benefit (e.g., dementia)?
Would patient-important outcomes or values about chemopreventive medications differ substantially in the subpopulation defined by [the targeting factor]?
Intervention Potential drivers of heterogeneity of intervention effects
Baseline risk Vulnerability/risk of harms Variable responsiveness to preventive intervention Specific primary and patient-important outcomes
E. When might complex interventions for potentially fatal or disabling conditions result in differing net benefits for subpopulations defined by agea, race-ethnicity, sex, or other targeting factors?
Identify complex intervention candidates Is [the targeting factor] a marker for selected deleterious health events that are amenable to complex interventions? Is [the targeting factor] also a marker for potential harms from complex interventions? Do complex interventions require certain supports and systems that vary by [the targeting factor] in order to be effective? Are there barriers or facilitators of complex interventions that vary by [the targeting factor]?
Complex or behavioral intervention delivery Is [the targeting factor] associated with increased baseline risk of some adverse health events (e.g., falls prevention, suicide, fatal motor vehicle accidents if age is the targeting factor)? Most interventions have few harms other than opportunity costs. Are there any harms related to [the targeting factor] that may not be hypothesized (e.g., increased visual acuity correction as an age-related harm)? Do certain conditions (e.g., dementia), decreased function, or inadequate environmental support affect intervention effectiveness? Would patient-important outcomes from or values about complex or behavioral interventions differ substantially in the subpopulation defined by [the targeting factor]?
  1. aExtremes of older age are often a proxy for reduced life expectancy, although multiple comorbidities may also be a marker for this state. Reduced life expectancy can be an additional subpopulation factor modifying potential net benefit for preventive topics in which time to benefit is prolonged, particularly when the harms are likely in a shorter time frame.