Evidence-based guideline: assessment and management of psychiatric disorders in individuals with MS. Report of the Guideline Development Subcommittee of the American Academy of Neurology

Screening and Diagnosis

What Clinical Evaluation Procedures and Screening and Diagnostic Tools Can Be Used to Accurately Identify Symptoms and Make Diagnoses of Emotional Disorders in Individuals with Multiple Sclerosis (MS)?

Conclusions and Recommendations

In individuals with MS, the Center for Neurologic Study Emotional Lability Scale (CNS-LS) is possibly effective and may be considered for screening for pseudobulbar affect (PBA) (Level C, 1 Class II study [Smith et al., 2004]). The General Health Questionnaire (GHQ) (Goldberg & Hillier, 1979) is possibly effective and may be considered for identifying individuals with broadly defined emotional disturbances (Level C, 1 Class II study [Rabins & Brooks, 1981]). The Beck Depression Inventory (BDI) (Beck et al., 1961) and a 2-question screen (Whooley et al., 1997) are possibly effective and may be considered for identifying individuals with major depressive disorder (MDD) (Level C, 1 Class II study each [Sullivan et al., 1995; Mohr et al., 2007]). There is insufficient evidence to support/refute using the Center for Epidemiologic Studies Depression Rating Scale (CES-D) (Radloff, 1977) to screen for depressive symptoms (Pandya, Metz, & Patten, 2005) or a single question to screen for MDD (Vahter et al., 2007) (Level U, 1 Class III study each); the possibility that somatic or neurovegetative symptoms negatively affect the accuracy of BDI results (Level U, 2 conflicting Class III studies) (Mohr et al., 1997; Randolph et al., 2000); and the use of specific instruments or clinical evaluation procedures to diagnose emotional disorders in individuals with MS (Level U).

Clinical Context

Because emotional disorders may be unrecognized in medical settings, validated screening tools might improve identification of individuals who could benefit from further evaluation and treatment. The true positive rate of a screening tool depends not only on its sensitivity but also on the point prevalence of the disorder in the population under study. Clinically, false-positive results are not a major concern because individuals with the conditions typically identified (e.g., adjustment and subthreshold depressive disorders) can benefit from further assessment. Administratively, however, screening tools with high false-positive rates unnecessarily increase resource use.

Treatments

What Are the Effective Treatments for Disorders of Mood in Individuals with MS?

Conclusion and Recommendations

For individuals with MS, a 16-week program of individual telephone-administered cognitive behavioral therapy (T-CBT) program is possibly effective and may be considered in treating depressive symptoms (Level C, 1 Class II study [Mohr et al., 2005], 1 Class III study [Mohr, et al., 2000]). There is insufficient evidence to support/refute the efficacy and use of 1) sertraline (Mohr et al., 2001), desipramine (Schiffer & Wineman, 1990), paroxetine (Ehde et al., 2008), individual in-person cognitive behavioral therapy (CBT) (Mohr et al., 2001), individual in-person CBT plus relaxation training (Foley et al., 1987), or CBT-based group therapy (Forman & Lincoln, 2010) for depressive symptoms; or 2) individual in-person CBT plus relaxation training (Foley et al., 1987), group relaxation and imagery (Maguire, 1996), or CBT-based group therapy (Forman & Lincoln, 2010) for anxiety (Level U, 1 Class III study each).

Clinical Context

There is evidence supporting the efficacy of pharmacologic and nonpharmacologic therapies for depressed mood and anxiety in individuals without MS. Despite the lack of evidence in individuals with MS, these therapies are frequently used to treat emotional disorders in this population.

What Are the Effective Treatments for Disorders of Affect in Individuals with MS?

Conclusion and Recommendations

Dextromethorphan and quinidine (DM/Q) is possibly effective and safe and may be considered for treating individuals with MS with PBA (Level C, 1 Class II study) (Panitch et al., 2006).

Clinical Context

DM/Q is the only drug approved by the US Food and Drug Administration for PBA treatment, although other drugs are used in clinical practice (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants). There are no randomized placebo-controlled trials of these other agents.

Definitions:

Classification of Evidence

Screening Articles

Class I: A statistical, population based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class II: A statistical, non-referral clinic based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion or a case report.

Diagnostic Articles

Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient's clinical status. Study results allow calculation of measures of diagnostic accuracy.

Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy.

Class IV: Studies not meeting Class I, II, or III criteria including consensus, expert opinion, or a case report.

Therapeutic Articles

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Screening and Diagnosis

What Clinical Evaluation Procedures and Screening and Diagnostic Tools Can Be Used to Accurately Identify Symptoms and Make Diagnoses of Emotional Disorders in Individuals with Multiple Sclerosis (MS)?

Conclusions and Recommendations

In individuals with MS, the Center for Neurologic Study Emotional Lability Scale (CNS-LS) is possibly effective and may be considered for screening for pseudobulbar affect (PBA) (Level C, 1 Class II study [Smith et al., 2004]). The General Health Questionnaire (GHQ) (Goldberg & Hillier, 1979) is possibly effective and may be considered for identifying individuals with broadly defined emotional disturbances (Level C, 1 Class II study [Rabins & Brooks, 1981]). The Beck Depression Inventory (BDI) (Beck et al., 1961) and a 2-question screen (Whooley et al., 1997) are possibly effective and may be considered for identifying individuals with major depressive disorder (MDD) (Level C, 1 Class II study each [Sullivan et al., 1995; Mohr et al., 2007]). There is insufficient evidence to support/refute using the Center for Epidemiologic Studies Depression Rating Scale (CES-D) (Radloff, 1977) to screen for depressive symptoms (Pandya, Metz, & Patten, 2005) or a single question to screen for MDD (Vahter et al., 2007) (Level U, 1 Class III study each); the possibility that somatic or neurovegetative symptoms negatively affect the accuracy of BDI results (Level U, 2 conflicting Class III studies) (Mohr et al., 1997; Randolph et al., 2000); and the use of specific instruments or clinical evaluation procedures to diagnose emotional disorders in individuals with MS (Level U).

Clinical Context

Because emotional disorders may be unrecognized in medical settings, validated screening tools might improve identification of individuals who could benefit from further evaluation and treatment. The true positive rate of a screening tool depends not only on its sensitivity but also on the point prevalence of the disorder in the population under study. Clinically, false-positive results are not a major concern because individuals with the conditions typically identified (e.g., adjustment and subthreshold depressive disorders) can benefit from further assessment. Administratively, however, screening tools with high false-positive rates unnecessarily increase resource use.

Treatments

What Are the Effective Treatments for Disorders of Mood in Individuals with MS?

Conclusion and Recommendations

For individuals with MS, a 16-week program of individual telephone-administered cognitive behavioral therapy (T-CBT) program is possibly effective and may be considered in treating depressive symptoms (Level C, 1 Class II study [Mohr et al., 2005], 1 Class III study [Mohr, et al., 2000]). There is insufficient evidence to support/refute the efficacy and use of 1) sertraline (Mohr et al., 2001), desipramine (Schiffer & Wineman, 1990), paroxetine (Ehde et al., 2008), individual in-person cognitive behavioral therapy (CBT) (Mohr et al., 2001), individual in-person CBT plus relaxation training (Foley et al., 1987), or CBT-based group therapy (Forman & Lincoln, 2010) for depressive symptoms; or 2) individual in-person CBT plus relaxation training (Foley et al., 1987), group relaxation and imagery (Maguire, 1996), or CBT-based group therapy (Forman & Lincoln, 2010) for anxiety (Level U, 1 Class III study each).

Clinical Context

There is evidence supporting the efficacy of pharmacologic and nonpharmacologic therapies for depressed mood and anxiety in individuals without MS. Despite the lack of evidence in individuals with MS, these therapies are frequently used to treat emotional disorders in this population.

What Are the Effective Treatments for Disorders of Affect in Individuals with MS?

Conclusion and Recommendations

Dextromethorphan and quinidine (DM/Q) is possibly effective and safe and may be considered for treating individuals with MS with PBA (Level C, 1 Class II study) (Panitch et al., 2006).

Clinical Context

DM/Q is the only drug approved by the US Food and Drug Administration for PBA treatment, although other drugs are used in clinical practice (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants). There are no randomized placebo-controlled trials of these other agents.

Definitions:

Classification of Evidence

Screening Articles

Class I: A statistical, population based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class II: A statistical, non-referral clinic based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion or a case report.

Diagnostic Articles

Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient's clinical status. Study results allow calculation of measures of diagnostic accuracy.

Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy.

Class IV: Studies not meeting Class I, II, or III criteria including consensus, expert opinion, or a case report.

Therapeutic Articles

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Screening and Diagnosis

What Clinical Evaluation Procedures and Screening and Diagnostic Tools Can Be Used to Accurately Identify Symptoms and Make Diagnoses of Emotional Disorders in Individuals with Multiple Sclerosis (MS)?

Conclusions and Recommendations

In individuals with MS, the Center for Neurologic Study Emotional Lability Scale (CNS-LS) is possibly effective and may be considered for screening for pseudobulbar affect (PBA) (Level C, 1 Class II study [Smith et al., 2004]). The General Health Questionnaire (GHQ) (Goldberg & Hillier, 1979) is possibly effective and may be considered for identifying individuals with broadly defined emotional disturbances (Level C, 1 Class II study [Rabins & Brooks, 1981]). The Beck Depression Inventory (BDI) (Beck et al., 1961) and a 2-question screen (Whooley et al., 1997) are possibly effective and may be considered for identifying individuals with major depressive disorder (MDD) (Level C, 1 Class II study each [Sullivan et al., 1995; Mohr et al., 2007]). There is insufficient evidence to support/refute using the Center for Epidemiologic Studies Depression Rating Scale (CES-D) (Radloff, 1977) to screen for depressive symptoms (Pandya, Metz, & Patten, 2005) or a single question to screen for MDD (Vahter et al., 2007) (Level U, 1 Class III study each); the possibility that somatic or neurovegetative symptoms negatively affect the accuracy of BDI results (Level U, 2 conflicting Class III studies) (Mohr et al., 1997; Randolph et al., 2000); and the use of specific instruments or clinical evaluation procedures to diagnose emotional disorders in individuals with MS (Level U).

Clinical Context

Because emotional disorders may be unrecognized in medical settings, validated screening tools might improve identification of individuals who could benefit from further evaluation and treatment. The true positive rate of a screening tool depends not only on its sensitivity but also on the point prevalence of the disorder in the population under study. Clinically, false-positive results are not a major concern because individuals with the conditions typically identified (e.g., adjustment and subthreshold depressive disorders) can benefit from further assessment. Administratively, however, screening tools with high false-positive rates unnecessarily increase resource use.

Treatments

What Are the Effective Treatments for Disorders of Mood in Individuals with MS?

Conclusion and Recommendations

For individuals with MS, a 16-week program of individual telephone-administered cognitive behavioral therapy (T-CBT) program is possibly effective and may be considered in treating depressive symptoms (Level C, 1 Class II study [Mohr et al., 2005], 1 Class III study [Mohr, et al., 2000]). There is insufficient evidence to support/refute the efficacy and use of 1) sertraline (Mohr et al., 2001), desipramine (Schiffer & Wineman, 1990), paroxetine (Ehde et al., 2008), individual in-person cognitive behavioral therapy (CBT) (Mohr et al., 2001), individual in-person CBT plus relaxation training (Foley et al., 1987), or CBT-based group therapy (Forman & Lincoln, 2010) for depressive symptoms; or 2) individual in-person CBT plus relaxation training (Foley et al., 1987), group relaxation and imagery (Maguire, 1996), or CBT-based group therapy (Forman & Lincoln, 2010) for anxiety (Level U, 1 Class III study each).

Clinical Context

There is evidence supporting the efficacy of pharmacologic and nonpharmacologic therapies for depressed mood and anxiety in individuals without MS. Despite the lack of evidence in individuals with MS, these therapies are frequently used to treat emotional disorders in this population.

What Are the Effective Treatments for Disorders of Affect in Individuals with MS?

Conclusion and Recommendations

Dextromethorphan and quinidine (DM/Q) is possibly effective and safe and may be considered for treating individuals with MS with PBA (Level C, 1 Class II study) (Panitch et al., 2006).

Clinical Context

DM/Q is the only drug approved by the US Food and Drug Administration for PBA treatment, although other drugs are used in clinical practice (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants). There are no randomized placebo-controlled trials of these other agents.

Definitions:

Classification of Evidence

Screening Articles

Class I: A statistical, population based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class II: A statistical, non-referral clinic based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion or a case report.

Diagnostic Articles

Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient's clinical status. Study results allow calculation of measures of diagnostic accuracy.

Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy.

Class IV: Studies not meeting Class I, II, or III criteria including consensus, expert opinion, or a case report.

Therapeutic Articles

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).