Made by DATEXIS (Data Science and Text-based Information Systems) at Beuth University of Applied Sciences Berlin
Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
          Funded by The Federal Ministry for Economic Affairs and Energy; Grant: 01MD19013D, Smart-MD Project, Digital Technologies
           
        
The diagnosis of an anxiety disorder requires first ruling out an underlying medical cause. Diseases that may present similar to an anxiety disorder, including certain endocrine diseases (hypo- and hyperthyroidism, hyperprolactinemia), metabolic disorders (diabetes), deficiency states (low levels of vitamin D, B2, B12, folic acid), gastrointestinal diseases (celiac disease, non-celiac gluten sensitivity, inflammatory bowel disease), heart diseases, blood diseases (anemia), and brain degenerative diseases (Parkinson's disease, dementia, multiple sclerosis, Huntington's disease).
Also, several drugs can cause or worsen anxiety, whether in intoxication, withdrawal, or from chronic use. These include alcohol, tobacco, cannabis, sedatives (including prescription benzodiazepines), opioids (including prescription pain killers and illicit drugs like heroin), stimulants (such as caffeine, cocaine and amphetamines), hallucinogens, and inhalants.
The American Psychiatric Association introduced GAD as a diagnosis in the DSM-III in 1980, when anxiety neurosis was split into GAD and panic disorder. The definition in the DSM-III required uncontrollable and diffuse anxiety or worry that is excessive and unrealistic and persists for 1 month or longer. High rates in comorbidity of GAD and major depression led many commentators to suggest that GAD would be better conceptualized as an aspect of major depression instead of an independent disorder. Many critics stated that the diagnostic features of this disorder were not well established until the DSM-III-R. Since comorbidity of GAD and other disorders decreased with time, the DSM-III-R changed the time requirement for a GAD diagnosis to 6 months or longer. The DSM-IV changed the definition of "excessive worry" and the number of associated psychophysiological symptoms required for a diagnosis. Another aspect of the diagnosis the DSM-IV clarified was what constitutes a symptom as occurring "often". The DSM-IV also required difficulty controlling the worry to be diagnosed with GAD. The DSM-5 emphasized that excessive worrying had to occur more days than not and on a number of different topics. It has been stated that the constant changes in the diagnostic features of the disorder have made assessing epidemiological statistics such as prevalence and incidence difficult, as well as increasing the difficulty for researchers in identifying the biological and psychological underpinnings of the disorder. Consequently, making specialized medications for the disorder is more difficult as well. This has led to the continuation of GAD being medicated heavily with SSRIs.
The DSM-IV-TR diagnostic criteria for panic disorder require unexpected, recurrent panic attacks, followed in at least one instance by at least a month of a significant and related behavior change, a persistent concern of more attacks, or a worry about the attack's consequences. There are two types, one with and one without agoraphobia. Diagnosis is excluded by attacks due to a drug or medical condition, or by panic attacks that are better accounted for by other mental disorders.
The diagnostic criteria:
The essential feature is recurrent attacks of severe anxiety (panic), which are not restricted to any particular situation or set of circumstances and are therefore unpredictable.
The dominant symptoms include:
- sudden onset of palpitations
- chest pain
- choking sensations
- dizziness
- feelings of unreality (depersonalization or derealization)
- secondary fear of dying, losing control, or going mad
Panic disorder should not be given as the main diagnosis if the person has a depressive disorder at the time the attacks start; in these circumstances, the panic attacks are probably secondary to depression.
The Panic Disorder Severity Scale (PDSS) is a questionnaire for measuring the severity of panic disorder.
Generalized anxiety disorder "F41.1"
Note: For children different criteria may be applied (see F93.80).
Anxiety disorders are often severe chronic conditions, which can be present from an early age or begin suddenly after a triggering event. They are prone to flare up at times of high stress and are frequently accompanied by physiological symptoms such as headache, sweating, muscle spasms, tachycardia, palpitations, and hypertension, which in some cases lead to fatigue.
In casual discourse the words "anxiety" and "fear" are often used interchangeably; in clinical usage, they have distinct meanings: "anxiety" is defined as an unpleasant emotional state for which the cause is either not readily identified or perceived to be uncontrollable or unavoidable, whereas "fear" is an emotional and physiological response to a recognized external threat. The term "anxiety disorder" includes fears (phobias) as well as anxieties.
The diagnosis of anxiety disorders is difficult because there are no objective biomarkers, it is based on symptoms, which typically need to be present at least six months, be more than would be expected for the situation, and decrease functioning. Several generic anxiety questionnaires can be used to detect anxiety symptoms, such as the State-Trait Anxiety Inventory (STAI), the Generalized Anxiety Disorder 7 (GAD-7), the Beck Anxiety Inventory (BAI), the Zung Self-Rating Anxiety Scale, and the Taylor Manifest Anxiety Scale. Other questionnaires combine anxiety and depression measurement, such as the Hamilton Anxiety Rating Scale, the Hospital Anxiety and Depression Scale (HADS), the Patient Health Questionnaire (PHQ), and the Patient-Reported Outcomes Measurement Information System (PROMIS). Examples of specific anxiety questionnaires include the Liebowitz Social Anxiety Scale (LSAS), the Social Interaction Anxiety Scale (SIAS), the Social Phobia Inventory (SPIN), the Social Phobia Scale (SPS), and the Social Anxiety Questionnaire (SAQ-A30).
Anxiety disorders often occur along with other mental disorders, in particular depression, which may occur in as many as 60% of people with anxiety disorders. The fact that there is considerable overlap between symptoms of anxiety and depression, and that the same environmental triggers can provoke symptoms in either condition, may help to explain this high rate of comorbidity.
Studies have also indicated that anxiety disorders are more likely among those with family history of anxiety disorders, especially certain types.
Sexual dysfunction often accompanies anxiety disorders, although it is difficult to determine whether anxiety causes the sexual dysfunction or whether they arise from a common cause. The most common manifestations in individuals with anxiety disorder are avoidance of intercourse, premature ejaculation or erectile dysfunction among men and pain during intercourse among women. Sexual dysfunction is particularly common among people affected by panic disorder (who may fear that a panic attack will occur during sexual arousal) and posttraumatic stress disorder.
Panic disorder typically begins during early adulthood; roughly half of all people who have panic disorder develop the condition before age 24, especially those subjected to traumatic experiences. However, some sources say that the majority of young people affected for the first time are between the ages of 25 and 30. Women are twice as likely as men to develop panic disorder and it occurs more often in people with above average intelligence.
Panic disorder can continue for months or years, depending on how and when treatment is sought. If left untreated, it may worsen to the point where one's life is seriously affected by panic attacks and by attempts to avoid or conceal the condition. In fact, many people have had problems with personal relationships or employment while struggling to cope with panic disorder. Some people with panic disorder may conceal their condition because of the stigma of mental illness. In some individuals, symptoms may occur frequently for a period of months or years, then many years may pass without symptoms. In some cases, the symptoms persist at the same level indefinitely. There is also some evidence that many individuals (especially those who develop symptoms at an early age) may experience symptom cessation later in life (e.g. past age 50).
In 2000, the World Health Organization found prevalence and incidence rates for panic disorder to be very similar across the globe. Age-standardized prevalence per 100,000 ranged from 309 in Africa to 330 in East Asia for men and from 613 in Africa to 649 in North America, Oceania, and Europe for women.
Accurately assessing for a specific Depressive Disorder diagnosis requires an expenditure of time that is deemed unreasonable for most primary care physicians. For this reason, physicians often use this code as a proxy for a more thorough diagnosis. There is concern that this may lead to a "wastebasket" mindset for certain disorders. In addition reimbursement through Medicare may be lower for certain non specific diagnosis.
ICD-10 defines social phobia as a fear of scrutiny by other people leading to avoidance of social situations. The anxiety symptoms may present as a complaint of blushing, hand tremor, nausea or urgency of micturition. Symptoms may progress to panic attacks.
Standardized rating scales such as the Social Phobia Inventory, the SPAI-B, Liebowitz Social Anxiety Scale, and the Social Interaction Anxiety Scale can be used to screen for social anxiety disorder and measure the severity of anxiety.
In the opinion of Allen Frances, chair of the DSM-IV task force, the DSM-5's somatic symptom disorder brings with it a risk of mislabeling a sizable proportion of the population as mentally ill. “Millions of people could be mislabeled, with the burden falling disproportionately on women, because they are more likely to be casually dismissed as ‘catastrophizers’ when presenting with physical symptoms.”
Prevention of anxiety disorders is one focus of research. Use of CBT and related techniques may decrease the number of children with social anxiety disorder following completion of prevention programs.
Questionnaires and checklists such as the Beck Depression Inventory or the Children's Depression Inventory can be used by a mental health provider to help detect, and assess the severity of depression. The Seasonal Pattern Assessment Questionnaire can be used to screen for seasonal affective disorder. Semi structured interviews such as the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) and the Structured Clinical Interview for DSM-IV (SCID) are used for diagnostic confirmation of depression.
Somatic symptom disorder has been a controversial diagnosis, since it was historically based primarily on negative criteria - that is, the absence of a medical explanation for the presenting physical complaints. Consequently, any person suffering from a poorly understood illness can potentially fulfill the criteria for this psychiatric diagnosis, even if they exhibit no psychiatric symptoms in the conventional sense. In 2013-4, there were several widely publicized cases of individuals being involuntarily admitted to psychiatric wards on the basis of this diagnosis alone. This has raised concerns about the consequences of potential misuse of this diagnostic category.
There are various treatments available to calm racing thoughts, some of which involve medication. One type of treatment involves writing out the thoughts onto paper. Some treatments suggest using activities, such as painting, cooking, and other hobbies, to keep the mind busy and distract from the racing thoughts. Exercise may be used to tire the person, thereby calming their mind. When racing thoughts are anxiety induced during panic or anxiety attacks, it is recommended that the person wait it out. Using breathing and meditation techniques to calm the breath and mind simultaneously is another tool for handling racing thoughts induced by anxiety attacks. Mindfulness meditation has also shown to help with racing thoughts by allowing practitioners to face their thoughts head-on, without reacting.
While all of these techniques can be useful to cope with racing thoughts, it may prove necessary to seek medical attention and counsel. Since racing thoughts are associated with many other underlying mental illnesses, such as bipolar disorder, anxiety disorder, and ADHD, medications used commonly to treat these disorders will help calm racing thoughts in patients.
Treatment for the underlying causes of racing thoughts is helpful and useful in order to calm the racing thoughts more permanently. For example, in people with ADHD, medications used to promote focus and calm distracting thoughts, will help them with their ADHD. Also, people with insomnia who have resulting racing thoughts will find Sleep Apnea treatment & Nasal surgery helpful to eliminate their racing thoughts. It is important to look at the underlying defect that may be causing your racing thoughts in order to prevent them long-term.
Anxiety disorder, the most common mental illness in the United States, affects 40 million people, ages 10 and older; this accounts for 18% of the U.S. population. Most people suffering from anxiety disorder report some form of racing thoughts symptom
The prevalence of OCD in every culture studied is at least 2% of the population, and the majority of those have obsessions, or racing thoughts. With these reportings, estimates of more than 2 million people in the United States (as of 2000) suffer from racing thoughts.
The "Diagnostic and Statistical Manual of Mental Disorders" (DSM-IV) recognizes two types of bipolar disorders—bipolar I and bipolar II. People with bipolar I disorder suffer from at least one manic or mixed episode, and may experience depressive episodes. On the contrary, as noted above, people with bipolar II disorder experience a milder form of a manic episode, known as a hypomanic episode as well as major depressive episodes. Although bipolar II is thought to be less severe than bipolar I in regards to symptom intensity, it is actually more severe and distressing with respect to episode frequency and overall course. Those with bipolar II often experience more frequent bouts of depressive episodes. Specific criteria defined by the DSM-IV for a bipolar II diagnosis is as follows:
- The presence of a hypomanic or major depressive episode.
- If currently in major depressive episode, history of a hypomanic episode. If currently in a hypomanic episode, history of a major depressive episode. No history of a manic episode.
- Significant stress or impairment in social, occupational, or other important areas of functioning.
Studies have identified major differences between bipolar I and bipolar II in regards to their clinical features, comorbidity rates and family histories. According to Baek et al. (2011), during depressive episodes, bipolar II patients tend to show higher rates of psychomotor agitation, guilt, shame, suicidal ideation, and suicide attempts. Bipolar II patients have shown higher lifetime comorbidity rates of DSM axis I diagnoses such as phobias, anxiety disorders, substance & alcohol abuse, and eating disorders and there is a higher correlation between bipolar II patients and family history of psychiatric illness, including major depression and substance-related disorders. The occurrence rate of psychiatric illness in first degree relatives of bipolar II patients was 26.5%, versus 15.4% in bipolar I patients.
Screening instruments like the Mood Disorders Questionnaire (MDQ) are helpful tools in determining a patient's status on the bipolar spectrum and getting families involved can also improve chances of an accurate diagnosis and acknowledgment of hypomanic episodes. In addition, there are certain features that have been shown to increase the chances that depressed patients are suffering from a bipolar disorder including atypical symptoms of depression like hypersomnia and hyperphagia, a family history of bipolar disorder, medication-induced hypomania, recurrent or psychotic depression, antidepressant refractory depression, and early or postpartum depression.
Psychosis as a symptom of a psychiatric disorder is first and foremost a diagnosis of exclusion. So a new-onset episode of psychosis "cannot" be considered to be a symptom of a psychiatric disorder until other relevant and known medical causes of psychosis are excluded, or ruled out. Many clinicians improperly perform, or entirely miss this step, introducing avoidable diagnostic error and misdiagnosis.
An initial assessment includes a comprehensive history and physical examination. Although no biological laboratory tests exist which confirm schizoaffective disorder, biological tests should be performed to exclude psychosis associated with or caused by substance use, medications, toxins or poisons, surgical complications, or other medical illnesses. Since non-medical mental health practitioners are not trained to exclude medical causes of psychosis, people experiencing psychosis should be referred to an emergency department or hospital.
Delirium should be ruled out, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, indicating other underlying factors which includes medical illnesses. Excluding medical illnesses associated with psychosis is performed by using blood tests to measure:
- Thyroid-stimulating hormone to exclude hypo- or hyperthyroidism,
- Basic electrolytes and serum calcium to rule out a metabolic disturbance,
- Full blood count including ESR to rule out a systemic infection or chronic disease, and
- Serology to exclude syphilis or HIV infection.
Other investigations which may be performed include:
- EEG to exclude epilepsy, and an
- MRI or CT scan of the head to exclude brain lesions.
Blood tests are not usually repeated for relapse in people with an established diagnosis of schizoaffective disorder, unless there is a specific "medical" indication. These may include serum BSL if olanzapine has previously been prescribed, thyroid function if lithium has previously been taken to rule out hypothyroidism, liver function tests if chlorpromazine has been prescribed, CPK levels to exclude neuroleptic malignant syndrome, and a urinalysis and serum toxicology screening if substance use is suspected. Assessment and treatment may be done on an outpatient basis; admission to an inpatient facility is considered if there is a risk to self or others.
Because psychosis may be precipitated or exacerbated by common classes of psychiatric medications, such as antidepressants, ADHD stimulant medications, and sleep medications, prescribed medication-induced psychosis should be ruled out, particularly for first-episode psychosis. This is an essential step to reduce diagnostic error and to evaluate potential medication sources of further patient harm. Regarding prescribed medication sources of patient harm, Yale School of Medicine Professor of Psychiatry Malcolm B. Bowers, Jr, MD wrote:
Illicit drugs aren't the only ones that precipitate psychosis or mania—prescribed drugs can too, and in particular, some psychiatric drugs. We investigated this and found that about 1 in 12 psychotic or manic patients in an inpatient psychiatric facility are there due to antidepressant-induced psychosis or mania. That's unfortunate for the field [of psychiatry] and disastrous for some of our patients.
Substance-induced psychosis should also be ruled out. Both substance- and medication-induced psychosis can be excluded to a high level of certainty while the person is psychotic, typically in an emergency department, using both a
- Broad spectrum urine toxicology screening, and a
- Full serum toxicology screening (of the blood).
Some dietary supplements may also induce psychosis or mania, but cannot be ruled out with laboratory tests. So a psychotic person's family, partner, or friends should be asked whether he or she is currently taking any dietary supplements.
Common mistakes made when diagnosing psychotic patients include:
- Not properly excluding delirium,
- Missing a toxic psychosis by not screening for substances "and" medications,
- Not appreciating medical abnormalities (e.g., vital signs),
- Not obtaining a medical history and family history,
- Indiscriminate screening without an organizing framework,
- Not asking family or others about dietary supplements,
- Premature diagnostic closure, and
- Not revisiting or questioning the initial diagnostic impression of primary psychiatric disorder.
Only after these relevant and known causes of psychosis have been ruled out can a psychiatric differential diagnosis be made. A mental health clinician will incorporate family history, observation of a psychotic person's behavior while the person is experiencing active symptoms, to begin a psychiatric differential diagnosis. Diagnosis also includes self-reported experiences, as well as behavioral abnormalities reported by family members, friends, or significant others. Mistakes in this stage include:
- Not screening for dissociative disorders. Dissociative identity disorder and psychotic symptoms in schizoaffective disorder have considerable overlap, yet a different overall treatment approach.
It is possible for this disorder to progress over time. A patient suffering from the disorder can improve the condition with treatments. There are several types of therapies that may improve the condition, but depending on a patient’s experience of the disorder or the cause of the disorder, treatments will vary.
- Psychotherapy including behaviour therapy, Gestalt therapy, Adlerian therapy, psychoanalytic therapy and existential therapy.
- Pharmacotherapy through medications including antidepressants.
There have been very few studies conducted to examine the possible causes of Bipolar II. Those that have been done have not considered Bipolar I and Bipolar II separately and have had inconclusive results. Researchers have found that patients with either Bipolar I or II may have increased levels of blood calcium concentrations, but the results are inconclusive. The studies that have been conducted did not find a significant difference between those with Bipolar I or Bipolar II. There has been a study looking at genetics of Bipolar II disorder and the results are inconclusive; however, scientists did find that relatives of people with Bipolar II are more likely to develop the same bipolar disorder or major depression rather than developing Bipolar I disorder.
The past DSM-IV criteria for IED were similar to the current criteria, however verbal aggression was not considered as part of the diagnostic criteria. The DSM-IV diagnosis was characterized by the occurrence of discrete episodes of failure to resist aggressive impulses that result in violent assault or destruction of property. Additionally, the degree of aggressiveness expressed during an episode should be grossly disproportionate to provocation or precipitating psychosocial stressor, and, as previously stated, diagnosis is made when certain other mental disorders have been ruled out, e.g., a head injury, Alzheimer's disease, etc., or due to substance abuse or medication. Diagnosis is made using a psychiatric interview to affective and behavioral symptoms to the criteria listed in the DSM-IV.
The DSM-IV-TR was very specific in its definition of Intermittent Explosive Disorder which was defined, essentially, by exclusion of other conditions. The diagnosis required:
1. several episodes of impulsive behavior that result in serious damage to either persons or property, wherein
2. the degree of the aggressiveness is grossly disproportionate to the circumstances or provocation, and
3. the episodic violence cannot be better accounted for by another mental or physical medical condition.
Diagnosis is based on the self-reported experiences of the person followed by a clinical assessment. Psychiatric assessment includes a psychiatric history and some form of mental status examination. Since some medical and psychiatric conditions mimic the symptoms of DPD, clinicians must differentiate between and rule out the following to establish a precise diagnosis: temporal lobe epilepsy, panic disorder, acute stress disorder, schizophrenia, migraine, drug use, brain tumour or lesion. No laboratory test for depersonalization-derealization disorder currently exists.
The diagnosis of depersonalization disorder can be made with the use of the following interviews and scales:
The Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D) is widely used, especially in research settings. This interview takes about 30 minutes to 1.5 hours, depending on individual's experiences.
The Dissociative Experiences Scale (DES) is a simple, quick, self-administered questionnaire that has been widely used to measure dissociative symptoms. It has been used in hundreds of dissociative studies, and can detect depersonalization and derealization experiences.
The Dissociative Disorders Interview Schedule (DDIS) is a highly structured interview which makes DSM-IV diagnoses of somatization disorder, borderline personality disorder and major depressive disorder, as well as all the dissociative disorders. It inquires about positive symptoms of schizophrenia, secondary features of dissociative identity disorder, extrasensory experiences, substance abuse and other items relevant to the dissociative disorders. The DDIS can usually be administered in 30–45 minutes.
The Cambridge Depersonalization Scale (CDS) is a method for determining the severity of depersonalization disorder. It has been proven and accepted as a valid tool for the diagnosis of depersonalization disorder in a clinical setting. It is also used in a clinical setting to differentiate minor episodes of depersonalization from actual symptoms of the disorder. Due to the success of the CDS, a group of Japanese researchers underwent the effort to translate the CDS into the J-CDS or the Japanese Cambridge Depersonalization Scale. Through clinical trials the Japanese research team successfully tested their scale and determined its accuracy. One limitation is that the scale does not allow for the differentiation between past and present episodes of depersonalization. It should also be noted that it may be difficult for the individual to describe the duration of a depersonalization episode, and thus the scale may lack accuracy. The project was conducted in the hope that it would stimulate further scientific investigations into depersonalization disorder.
Routine medical assessments are often prescribed to rule-out or identify a somatic cause for bipolar I symptoms. These tests can include ultrasounds of the head, x-ray computed tomography (CAT scan), electroencephalogram, HIV test, full blood count, thyroid function test, liver function test, urea and creatinine levels and if patient is on lithium, lithium levels are taken. Drug screening includes recreational drugs, particularly synthetic cannabinoids, and exposure to toxins.
According to a substantial amount of epidemiology studies conducted, women are twice as likely to develop certain mood disorders, such as major depression. Although there is an equal number of men and women diagnosed with bipolar II disorder, women have a slightly higher frequency of the disorder.
In 2011, mood disorders were the most common reason for hospitalization among children aged 1–17 years in the United States, with approximately 112,000 stays. Mood disorders were top principal diagnosis for Medicaid super-utilizers in the United States in 2012. Further, a study of 18 States found that mood disorders accounted for the highest number of hospital readmissions among Medicaid patients and the uninsured, with 41,600 Medicaid patients and 12,200 uninsured patients being readmitted within 30 days of their index stay—a readmission rate of 19.8 per 100 admissions and 12.7 per 100 admissions, respectively. In 2012, mood and other behavioral health disorders were the most common diagnoses for Medicaid-covered and uninsured hospital stays in the United States (6.1% of Medicaid stays and 5.2% of uninsured stays).
A study conducted in 1988 to 1994 amongst young American adults involved a selection of demographic and health characteristics. A population-based sample of 8,602 men and women ages 17–39 years participated. Lifetime prevalence were estimated based on six mood measures:
1. major depressive episode (MDE) 8.6%,
2. major depressive disorder with severity (MDE-s) 7.7%,
3. dysthymia 6.2%,
4. MDE-s with dysthymia 3.4%,
5. any bipolar disorder 1.6%, and
6. any mood disorder 11.5%.
Depersonalization disorder is classified differently in the DSM-IV-TR and in the ICD-10: In the DSM-IV-TR this disorder it is seen as a dissociative disorder; in the ICD-10 as an independent neurotic disorder. Whether depersonalization disorder should be characterized as a dissociative disorder can be discussed.
DSM-5 diagnostic criteria for a panic attack include a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms developed abruptly and reached a peak within minutes:
- Palpitations, and/or accelerated heart rate
- Sweating
- Trembling or shaking
- Sensations of shortness of breath or being smothered
- Feeling of choking
- Chest pain or discomfort
- Nausea or abdominal distress
- Feeling dizzy, unsteady, lightheaded, or faint
- Derealization (feelings of unreality) or depersonalization (being detached from oneself)
- Fear of losing control or going insane
- Sense of impending death
- Paresthesias (numbness or tingling sensations)
- Chills or hot flashes
In DSM-5, culture-specific symptoms (e.g., tinnitus, neck soreness, headache, and uncontrollable screaming or crying) may be seen. Such symptoms should not count as one of the four required symptoms.
Some or all of these symptoms can be found in the presence of a pheochromocytoma.
Screening tools such as the Panic Disorder Severity Scale can be used to detect possible cases of disorder and suggest the need for a formal diagnostic assessment.
Although exact rates of prevalence are not available, general population data shows a 0.002% prevalence over a year-long period and higher prevalence within clinical populations.