Analytic Framework for Evaluating Effects of Cystic Fibrosis (CF) Newborn Screening
To evaluate the potential benefits and risks of newborn screening for CF, the Centers for Disease Control and Prevention (CDC) applied an analytic framework to interpret evidence of clinical utility (i.e., the net balance of health outcomes) of earlier identification and treatment (see figure in the original guideline document). This framework draws in part on the approach used by the U.S. Preventive Services Task Force (USPSTF). It considers both potential benefits and harms from screening; harms are classified separately as adverse effects from screening and those from diagnosis or treatment. The benefits of screening flow from early, asymptomatic detection and can be classified in terms of health benefits to the affected person and psychosocial benefits to persons and families. To classify health benefits, CDC used the Strength of Recommendations Taxonomy (SORT), a recently proposed patient-centered approach to grading evidence in medical literature (See "Rating Scheme for the Strength of the Recommendations" and "Rating Scheme for the Strength of the Evidence.") The SORT framework does not include psychosocial outcomes, which constitute key benefits and risks from newborn screening for CF and should be considered in policy recommendations.
The potential psychosocial risks of screening include factors associated with 1) false-positives (e.g., unnecessary testing and possibly unnecessary treatment for the child, undue parental anxiety, and desensitization of providers), 2) false-negatives (e.g., potential delay in diagnosis for child and false reassurance for patients), 3) carrier reporting (e.g., possibly unwanted information and fear of stigmatization or insurance discrimination), and 4) misinformation (e.g., errors in communication or misunderstanding of results). Potential harms to CF patients of early detection and treatment as a result of newborn screening include side effects of therapies (e.g., drug resistance and toxicities) and earlier exposure (through person-to-person transmission from older children with CF) to bacteria associated with chronic airway infection in CF.
The SORT taxonomy is used to assess the clinical effectiveness of interventions based on a structured review of research findings. The SORT framework categorizes studies into three levels (Levels 1, 2, and 3) on the basis of study design and type of outcomes assessed. The total evidence for an intervention is given one of three grades (A, B, or C) on the basis of the assigned levels of the individual studies.
The SORT taxonomy distinguishes two classes of health outcomes: 1) disease-oriented outcomes (e.g., intermediate, histopathologic, physiologic, or surrogate results) that might reflect improvements in patient outcomes and 2) patient-oriented outcomes (e.g., reduced morbidity, reduced mortality, symptom improvement, improved quality of life, or lower cost) that help patients live longer or better lives.
In the SORT framework, either a high-quality randomized controlled trial (RCT) or a meta-analysis of RCTs that demonstrates improved patient-oriented outcomes is considered Level-1 evidence. Information on patient-oriented outcomes from a lower-quality clinical trial, cohort study, or case-control study constitutes Level-2 evidence. All other types of research studies, including case series, are classified as Level 3, along with all studies, even RCTs, that provide information restricted to disease-oriented outcomes.
For the SORT framework to be applied, endpoints used in evaluations of newborn screening for CF are classified as either patient-oriented or disease-oriented. The approach taken in this report is to classify endpoints that are collected during routine clinical monitoring of individuals with CF as disease-oriented outcomes. These include measures of nutritional and pulmonary outcomes (e.g., height and weight, spirometric measures of lung function, and chest radiograph scores). In this analysis, survival, quality of life, and cost (including hospitalizations and invasive therapies) were classified as patient-oriented outcomes. Cognitive function, which is not routinely assessed in persons with CF, was also classified as a patient-oriented outcome because of its direct link to quality of life and because it is not a surrogate outcome in CF. The classification of certain endpoints as disease-oriented or patient-oriented outcomes has implications for assessment of evidence on newborn screening for CF. In particular, growth retardation might be regarded as both a patient-oriented outcome and a disease-oriented outcome. The high demand for expensive growth hormone therapy, which results in moderate gains in linear growth for children with CF who have low height-for- age , indicates that below-normal stature might be viewed as a patient-oriented outcome. In addition, growth retardation among children with CF has been demonstrated to be a strong predictor of survival. An RCT indicating reduction in growth retardation would be classified as Level-1 evidence if this outcome were classified as patient-oriented but as Level-3 evidence if it were classified as disease-oriented.