Two opposing agendas confront clinical labs in terms of electronic health records (EHRs): privacy/security on the one side, and interoperability, on the other. The former involves an inward push for isolation, while the latter tends to pull technology in the other direction.
There also is a major financial challenge. While healthcare providers have been given a host of incentives to adopt EHRs (especially in the US), labs have been pretty much left out on their own.

EHRs and lab systems populate different worlds
Clearly, lab-compatible EHR systems which meet both (privacy and interoperability) criteria promise the quickest returns. EHR developers have however shown little enthusiasm, until recently, to incorporate clinical lab requirements as a sufficient driver, while laboratory system vendors have tended to ignore EHRs or postpone taking them into account until EHR development has matured sufficiently. 

US EHR adoption drives lab applications
In the US, this limbo is being shaken up by healthcare providers, who are compelling vendors to take account of their need for EHR-friendly clinical lab systems.
At end 2012, the US Centers for Disease Control and Prevention (CDC) released a survey which found 72 percent of office-based physicians using EHR systems, up from 48 percent in 2009 and 18 percent in 2001. 
The reason for the dramatic increase in EHR adoption lies in the Meaningful Use requirements of the 2009 Health Information Technology for Economic and Clinical Health Act, also known as the HITECH Act. The Act provides billions of dollars in incentive payments through the Medicare and Medicaid programmes to increase physician adoption of EHR systems.

Clinical labs are now being lifted by the rising tide of EHR adoption. According to the US Office of the National Coordinator for Health Information Technology (ONC), the “availability of structured lab results within the EHR contributes to office efficiencies while also assisting providers in the ability to make real time decisions about the patient’s care.”
The ONC explicitly specifies the threshold for EHR-friendly clinical lab practices in Stage 1 – of over 40 percent of all lab test results ordered by a provider and incorporated in certified EHR technology as structured data.
Stage 2 Meaningful Use requirements, finalised in August 2012, increase the clinical lab results threshold to 50 percent. The ONC has subsequently announced plans to assess health information exchange (HIE) in clinical laboratories.

Labs left to own resources
While healthcare providers have the financial incentives of the HITECH Act, clinical labs have been left to their own resources to set up interfaces from their laboratory information systems (LIS) to providers.
Compounding this has been inconsistencies in the way different EHR systems generate lab test orders.
However, the alternative has been stark – to be left out of referrals from tests.

EHR systems remain heterogeneous
The US EHR landscape is however hardly uniform. As of September 2013, there were 3,652 non-enterprise certified ambulatory EHR software systems, almost half of which were classified as “complete” to qualify for Meaningful Use Stage 1 or Stage 2.
In spite of efforts to set standards for semantic interoperability of healthcare data, standards so far are only syntactic (based on HL7 and XML). 
The alternative, to develop a common US-wide EHR system, has been accepted as being technically insurmountable – due to hurdles in specifying, developing, testing and deploying standardized tools, common architectures and vocabularies, within secure, real-time and scalable networks, and doing all this within the fast-changing world of information and communications technologies.
For proponents of a decentralized approach to EHR technology, in the US in particular, the sharp increase in offtake of EHR systems has shown that it has delivered – as far as healthcare IT objectives are concerned.

EHR faces teething problems
Still, teething troubles for EHRs also clearly remain.
In early September 2013, one of the leading EHR systems, from EPIC, crashed across seven major healthcare facilities of Sutter Health, a nearly 100 year-old healthcare provider in California. Some suspect the role of a routine upgrade a few days earlier in the EHR system, which was launched by Sutter at a cost of $1.2 billion in 2004, but has so far reached only a halfway mark.

EHR challenges for labs remain to be resolved
Such issues with the evolution of maturity of EHRs pose especially major problems for labs, who (as mentioned) have to develop and fund interfaces between their LISs and the EHRs of their client physicians but are also forced to cope with the lack of uniform EHR standards.

Some vendors have nevertheless sought to fill the gap.
A leading example is HDD Access, a joint initiative by the US Department of Defense, the Department of Veterans Affairs and 3M Health Information Systems to create a public use version of 3M’s Healthcare Data Dictionary (HDD). HDD Access consists of a relational database and Application Programming Interface (API) runtime services to which other applications can interface. The terminology is organized as a controlled medical vocabulary – a comprehensive set of clinical and other concepts used in healthcare.
HDD Access offers specific benefits for integrating LIS and EHR platforms. Independent of source system, it can track local fields and translate them into laboratory concepts. Nevertheless, HDD Access warns that it is “not a standard terminology and is not a replacement for standard terminologies.

In effect, in the US, clinical labs are likely to continue to face a host of technical challenges with respect to EHRs in the years to come.

EHR Big Bang fizzles in Europe
Unlike the US, Europe made a massive effort in 2004 to devise common semantic standards for EHR interoperability as part of its Single eHealth Area. The EU’s EHR objectives sought to integrate all patient information – from primary to tertiary settings, and include emergency and in-patient care. Also on the radar were ambitious plans to connect pharmacies as well as the web of disparate billing/reimbursement procedures, and do so across Europe.
In mid–2008, the EU Commission set 2015 as the target year for EHR interoperability, to ensure that key EHR datasets could cross European borders, and do so in conformity with medical rules and other relevant legal frameworks.

In January 2011, however, these ambitions were put on the backburner, after an official report criticized the effort as being both impractical and ‘grandiose’. The report found that a pan-EU EHR system would neither be technically feasible, cost-effective or even medically justified, and instead urged more emphasis on decentralized efforts – in other words, just like the US.
Technical challenges aside, massive differences in physician and medical cultures across Europe played a major role in derailing efforts toward a common EHR. Or, as EuroRec, an umbrella organization tasked with pan-EU EHR implementation, states: it was “widely recognized that social and organizational aspects are as likely to ruin an implementation process as technical factors are.”

European focus shifts to national efforts
The EHR focus in Europe has now totally shifted to national efforts. A new eHealth Governance Initiative (eHGI) encourages cooperation “between Member States” and “between national authorities and standardization bodies”, and seeks to “enable the recommendation of standards and (harmonized) profiles based on selected use cases.” On the technical side, compared to the Big Bang efforts of the Single eHealth Area, it also aims to “link and harmonize coding systems” and “facilitate access to existing standards and medical vocabularies.”
The second area for Europe’s EHR focus is a minimalistic intra-EU/regional approach embodied in a project called epSOS, which dates back to 2008, but was (temporarily) eclipsed by the ambitions of the Single eHealth Area. epSOS, which went live in April 2012, has the modest goal of connecting 20 EU nations (and 3 non-EU members) to a secure database, and sharing only Patient Summaries and ePrescription records via IHE X* profiles. Its target consists of Europeans holidaying overseas.

Today, EHR adoption varies considerably in Europe. The Nordic countries have been using the technology for over a decade and are fairly advanced as a result in EHR implementation.
However, adoption in France, Germany, Spain and the UK is ‘on course’ with the US.

Shift from Single eHealth Area encourages new EHR-directed lab applications
The shift away from forcing through a Single eHealth Area has also opened the way for innovative working approaches aimed at clinical labs. One good example of this is Valle de los Pedroches Hospital at Cordoba, Spain, which has  designed and implemented a unified lab test request module for the Andalusian regional EHR.
In spite of some outstanding issues (such as rigidity in error solving, and the need to adapt to a new nomenclature), implementation of the laboratory module in the EHR improved the analytical process, with better patient safety and less programming or container errors and shorter response times. Clinical professionals gave a rating of 7.8 out of 10, positively highlighting the speed at which results are delivered and their integration in the EHR.
Such efforts are likely to grow with time.

There is growing interest in tumour markers as aids for the diagnosis, staging and management of cancer. Some are expected to succeed, after several years of evaluation to trials and eventual clinical use. A large number, however, are not likely to make it beyond development. On their part, physicians need to be aware of both opportunities and limitations in the clinical use of tumour markers.
Tumour markers are substances (antigens, proteins, enzymes or hormones) which indicate the presence of cancer or provide information about its likely course of development. They are present in cancerous tissue as well as in the bodily fluids of cancer patients.

Range of applications
Tumour markers have shown their potential for several applications. These range from the differential diagnosis of benign and malignant conditions to prognostic assessments, postoperative surveillance, the prediction of drug response or resistance, and the monitoring of therapy in
advanced disease.
The key advantage of tumour markers in the above applications is convenience. Inexpensive automated assays allow for fast processing of samples.

The case for tumour markers
The best known tumour markers include Her2/neu for breast cancer, which has an established economic case. Her-2/neu is a target for trastuzumab, whose use as an adjuvant has been shown to decrease cancer recurrence rates by 50%. However, up to one in 20 trastuzumab recipients develop cardiac dysfunction. Given that the cost of one year of therapy is close to 100,000 Euros, the need for accurately and precisely assaying every tissue sample is evidently strong.

Work in progress
Tumour markers are, however, still a work in progress and expected to remain so. In the US, the National Cancer Institute (NCI) states that “more than 20 tumour markers are currently in use.” It however lists over 30. The European Group on TumoUr Markers (EGTM) has a list of 16.
Despite the number of tumour markers in development, only ‘traditional’ markers are used in diagnosis, prognosis and monitoring. For example, at least six urine tumour marker kits are approved by the US Food and Drug Administration for bladder cancer. However, none are backed by data from clinical trials that increased survival time, improved quality of life or decreased cost of treatment.

Appropriate use, caution urged
Many experts urge caution with respect to tumour markers. Inappropriate use, according to an article in the ‘British Medical Journal’, can cause patients unnecessary anxiety and distress, and may also delay correct diagnosis and treatment. The authors cite one hospital audit which found “that only about 10% of requests for tumour markers were appropriate.”
The European Group on Tumor Markers attributes part of this problem to the growing availability of automated immunoassays. This makes tumour marker tests available in routine rather than specialist laboratories. “Results are consequently more readily available to non-specialist clinicians, who may be less familiar with their interpretation.”

Challenges of sensitivity and specificity
Only some markers, known as tumour-specific markers, are produced exclusively by a particular tumour As a result, most tumours cannot be detected by a single test, and tests for multiple markers are often required.
Tests are therefore often accompanied by the risk of both false positives and false negatives. The Cancer Information & Support Network (CISN) sums up the picture: False positives may occur because most tumour markers “can be made by normal cells, as well as cancer cells,” and markers “can be associated with noncancerous conditions.” On the other hand, the reason for false negatives is that “tumour markers are not always present in early stage cancers” and because “people with cancer may never have elevated tumour markers.”
For example, the level of CA-125, a marker for ovarian cancer, is also elevated in a variety of non-malignant disorders such as cirrhosis, pancreatitis, endometriosis, and pelvic inflammatory disease. In addition, medications appear to alter the results of a varied range of tests. So too do pregnancy, menstruation, cigarette smoking and various benign disorders.

Biopsy remains only definitive way for diagnosis
The above lack of sensitivity and specificity has been a major limitation facing the use of tumour markers in clinical practice. As with imaging, the use of tumour markers has been limited to supporting the diagnostic process, and the gold standard for diagnosis still remains a biopsy.
Although difficult to access areas such as the brain are likely to result in more use of tumour markers, a biopsy remains “the only definitive way” for diagnosis of a tumour” even in the brain.

NACB Guidelines
In 2008, the National Academy of Clinical Biochemistry (NACB) in the US released updated Laboratory Medicine Practice Guidelines for the use of tumour markers.

The guidelines made cross-referrals to efforts by numerous professional and regulatory best-practices bodies, including the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN), Britain’s National Institute for Health and Clinical Excellence (NICE), the European Group on Tumor Markers (EGTM), the International Federation of Gynecology and Obstetrics (FIGO) and the Gynecologic Cancer Intergroup (GCIG).
The NACB guidelines cover five cancer sites: testicular, prostate, colorectal, breast, and ovarian.

Testicular cancer
For testicular cancer, α-fetoprotein (AFP), human chorionic gonadotropin and lactate dehydrogenase are recommended for diagnosis, staging, prognosis determination, recurrence detection and the monitoring of therapy. AFP is also recommended for the differential diagnosis of tumours

Prostate cancer
Prostate-specific antigen (PSA) is considered to be potentially useful for detecting prostate cancer recurrence and monitoring therapy. Free PSA is considered useful for distinguishing malignant from benign prostatic disease.

Colorectal cancer
In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, post-operative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing is considered useful for screening asymptomatic adults who are older than 50 years.

Breast cancer
For breast cancer, estrogen and progesterone receptors predict response to hormone therapy, human epidermal growth factor receptor-2 predicts response to trastuzumab, while urokinase plasminogen activator/ plasminogen activator inhibitor 1 is used for determining prognosis in lymph node-negative patients. CA15-3/BR27–29 or carcinoembryonic antigen can be used for therapy monitoring in advanced disease.

Ovarian cancer
CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in post-menopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer.

Future research to target higher specificity and sensitivity
In the future, research is expected to focus on finding markers which are specific of one pathology, have higher sensitivity with a low cut-off and deliver results which correlate to tumour mass and growth potential. Ideal candidates would also have a short life duration to permit efficient follow-up; in other words, their presence should decrease during treatment and increase before a relapse.

The promise and challenges of screening
Given that tumour markers can aid in assessing the response to cancer treatment and making prognoses, many public health professionals have hoped they might also be used for screening tests which would detect cancer before the presence of symptoms.
Indeed, many tests have both screening and diagnostic uses, with only the context of use determining whether the test is one or the other. “A screening test is done on asymptomatic individuals who receive the test principally because they are of the age or sex at risk for the cancer. A diagnostic test is done on an individual because of clinical suspicion of disease.”

However, no tumour marker identified to date is sufficiently sensitive or specific to be used on its own for screening, demonstrating a survival benefit in randomized controlled trials in the general population.

One of the best known examples is the prostate-specific antigen (PSA) test. Although it is now accepted that most men with elevated PSA levels do not have prostate cancer, the implications of this remain mired in controversy and also illustrate the kind of limitations which other tumour biomarkers may face in the future for use in screening.
PSA screening has been the subject of two large randomized controlled trials in the US and Europe in the 2000s. However, as the Mayo Clinic notes, in spite of the size of the trials, there were “no clear conclusions.” This is because their diversity of methodology allows for significant flexibility in interpretation. As a result, “the decision of whether to screen or not screen – using PSA testing or other means or both – is a decision best made between physicians and their individual patients.”

The two trials were PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) conducted by the National Cancer Institute in the US, and the European Randomized Study of Screening for Prostate Cancer (ERSPC), billed as “the largest randomized trial of screening for prostate cancer” with 162,388 subjects.
In 2011, a US government task-force concluded that healthy men should not be screened for prostate cancer. The finding, which “drastically changed the standard of care for middle-age American men who had grown accustomed to annual screenings,” was largely based on 10 years data from the two studies, which found risk of over-diagnosis and over-treatment.

Problems began when follow-on data from ERSPC two years later showed screening was associated “with a 21% reduction in risk of prostate cancer mortality.” However, this was accompanied by a still-sizeable risk of over-diagnosis and over-treatment. As a result, the authors said that “population-based screening could not yet be recommended.
In April 2015, an article in ‘The Lancet’ re-confirmed “a substantial 21% reduction” from PSA screening. However, due to access restrictions to the ERSPC trial data, the authors called this figure into serious question.

The controversy is unlikely to go away for some time. An Op Ed in The New York Times called the PSA test “hardly more effective than a coin toss.” Although the date of publication was 2010, the author of the commentary was Dr. Richard Ablin, who discovered PSA in 1970.
Such challenges are also likely to accompany screening for other conditions. For instance, data from the PLCO trial show that screening for CA-125 (recommended by the National Academy of Clinical Biochemistry for women with ovarian cancer, along with transvaginal ultrasound), does not reduce ovarian cancer mortality. Instead, false-positive screening test results have been associated with complications.

Molecular diagnostics is seen as the gateway to an era of personalized medicine.  It detects DNA and RNA-level abnormalities that provoke and fuel most diseases. As a result, it offers precise diagnosis, determines the susceptibility of a patient to a specific disease and assesses his or her response to therapy. Moelcular diagnostics can also establish a patient’s prognosis over time far more scientifically than what is often no more than a physician’s informed guess.

Tailored therapy, patient convenience
The track record of molecular diagnostics is, on first sight, impressive.
For instance, FoundationOne, a molecular diagnostic test from Foundation Medicine, scans a patient’s tumour sample for changes in 238 genes that drive cancers, helping oncologists to “choose drugs targeted to the genetic profile of a patient’s tumour cells.”
Another example is Cologuard, from Exact Sciences, which screens stool samples for colorectal cancer. Apart from greater accuracy, the technique is far less invasive than colonoscopy. According to The Mayo Clinic, this will enable more people to get tested earlier and ‘revolutionize’ the fight against colorectal cancer.
Convenience in access is also central to tests from TrovaGene, which utilizes urine samples. Priority targets for the company include malignant melanoma, whose rate of spread makes early detection invaluable, but is also an especially difficult cancer to diagnose via traditional means.

Genomic Health: single-product trailblazer
A poster child of the molecular diagnostic revolution is Genomic Health. The company was founded 15 years ago to close the gap between genomic research and real-life benefits for cancer patients.
Based on the success of a single product, Oncotype Dx, the company has reached a market value of about $1 billion. Oncotype Dx predicts relapse rates of women with breast cancer and assesses benefits from different types of chemotherapy. Its scope has also been extended to prostate and colon cancer.

Targeting broad spectrum of diseases
New molecular diagnostic products, however, go beyond cancer to other challenging conditions. Rheumatoid arthritis is the focus for Crescendo Bioscience, which has developed a test for 12 different proteins in a blood sample of patients. Its metrics are the first to measure molecular activity of the disease and permits a quicker decision to screen for antibodies. The test, moreover, can determine the effectiveness of a cheap, generic steroid such as dexamethasone on a particular patient, as it can about the ineffectiveness of biotech drugs – whose costs range from $1,000 to $3,000 a month.

In some cases, research breakthroughs have allowed firms to offer tests for a variety of diseases out of the same platform. The tests from TrovaGene, for example, are based on proprietary cell-free nucleic acid (cf-NA) techniques – and can be used for cancer as well as infectious disease, organ transplantation and prenatal genetic testing.

Regulation holds key to building confidence
In spite of its strong case, the proponents of molecular diagnostics lament that current use is far below potential. Such arguments have reached fever pitch, especially in the US.
The reason seems ironical. The industry has been calling for more government regulation. An Op-Ed piece in ‘The Boston Globe’ in 2011 explains why. Due to the absence of clear approval policies, it notes, both payers and physicians lacked confidence about the reliability and accuracy of molecular diagnostics. The authors of the Op-Ed, Mara Aspinall, then CEO of an IP-rich molecular diagnostics company On-Q-ity, and Brook Byers of venture capital powerhouse Kleiner, Perkins, Caufield & Byers, were especially scathing about the decision by the Food and Drug Administration (FDA) “to regulate diagnostic tests as ‘medical devices’,” and proposed that molecular diagnostics requires both “new expertise and a new regulatory focus.”
These kind of concerns seemed prescient. Within two years, Aspinall’s On-Q-ity had folded. Following its demise, an industry analyst observed that molecular diagnostics faced similar concerns as therapeutics, but was confronted “by larger reimbursement and regulatory uncertainties.”

CLIA certification and reimbursement
Many molecular diagnostic tests on the US market have not been endorsed by the FDA, or been classified as eligible for Medicare. Indeed, tests approved by the FDA largely concern infectious diseases and companion diagnostics.
Most vendors have their products certified under the less stringent Clinical Laboratory Improvement Amendments (CLIA) standard. Some have succeeded in obtaining Medicare reimbursement, with only CLIA certification. However, this has been lengthy. For example, Crescendo’s rheumatoid arthritis test discussed previously was sold for three years, before being approved by Medicare.
Others have fared worse, in spite of successful products on the market. Foundation Medicine’s tumour test (see above) is neither FDA-approved, nor reimbursed by Medicare. As a result, the company has to negotiate with payers to get paid every time a patient is tested with its product.

Multiple, complex challenges
There are several layers in the underlying problem.
The first is the regulation of diagnostic tests as medical devices. As explained by ‘Expert Review of Molecular Diagnostics’, current regulatory systems were written to regulate a broader array of products, and “molecular diagnostics are now being fitted into that existing framework.” Though there will be overlaps, it is  “appropriate to treat molecular diagnostics – properly defined – in a different manner to a group consisting of all other IVDs.” This is clearly not yet the case. A certification program at the University of California, San Diego, for example, notes: “Molecular diagnostics, or in vitro diagnostics …”.
A second regulatory challenge is that molecular diagnostics encompasses both test assays as well as instruments and equipment. The latter are more clearly akin to devices, assays far less so. However, a problem arises when instruments used in assay development are specifically referenced for approvals. A Draft Guidance from the FDA in April 2013 acknowledges such a limitation.
The third factor is the linkage between genomics research on biomarkers, which yields masses of data, but does not provide clinically useful information for real-world molecular diagnostics. This can only be achieved in a gray area between a research laboratory and a clinical laboratory.

Research use only versus diagnostics
The FDA regulates (in vitro) diagnostic kits explicitly designed for diagnostic use. In sharp contrast, research use only (RUO) products are unregulated. Their definition in FDA regulations covers labelling only and is sketchy, specifying that they should be “in the laboratory research phase of development and not represented as an effective in vitro diagnostic product.”
Biomarker assays are usually labelled RUO since their clinical use is unknown, until after their diagnostic effectiveness has been evaluated in a clinical laboratory. Some maintain this status indefinitely, staying outside FDA jurisdiction.
The regulatory problem arises once a clinical laboratory evaluation of a biomarker begins to move on its own course.

From in vitro to molecular diagnostics: difference in detail
As explained by Jeffrey Gibbs of the law firm Hyman, Phelps & McNamara, the roots of the RUO challenge date to the 1990s, when many RUO products began to be used by laboratories for clinical applications. At this time, companies labelled their in vitro assays and instruments as RUO but then promoted them for diagnostic use – in some cases, making specific claims too. 
In 1997, the FDA sought to curb this practice with a regulation on analyte specific reagents (ASR), targeting the basic chemical components used in diagnostic assays. However, it became clear some years later that the ASR regulation was being used to camouflage sales of more complex products. In 2007, the FDA issued a guidance document on ASRs, prohibiting the combination of more than one active component.
This, as Mr. Gibbs states, was acceptable for in vitro diagnostics. It was clearly not so for molecular diagnostics, where, for example, a primer and probe pair need to be offered together. To cope with this, a number of companies relabelled their ASRs as (unregulated) RUOs.

In a draft guidance in 2011, the FDA proposed sanctioning companies for selling RUO diagnostic products to clinical labs. Of special concerned were ‘high-risk’ laboratory-developed tests (LDTs) impacting on major treatment decisions – attention to which strengthened in 2011 after the prestigious Duke University used faulty genomic markers to select therapy for cancer patients.

FDA steps in, but industry remains uncertain
The end of 2013 saw a series of major moves by the FDA, which will have a bearing on the shape of the molecular diagnostics industry in the years to come.
One was to shut down health-related genetic tests by direct-to-consumer firms, including market leader 23andMe, which has been selling kits and test results for carrier status, health risks, and drug response.
Another was to provide the first-ever FDA clearance of a next-generation sequencing (NGS) instrument and universal reagents, opening the way for tests to be cleared on their own merits. This may encourage a move by companies of their RUO products into the FDA process.
The FDA also issued a Final Guidance on how companies could market RUO and investigational use only (IUO) diagnostic tests and instruments, which several clinical laboratories had been using for LDTs.

In its Guidance, the FDA backed off from its plans two years before to sanction RUO product sales to clinical laboratories. However, it opens the way for enforcement – and another kind of uncertainty for molecular diagnostic companies, for some time to come.
The Guidance notes that if a manufacturer “were to assist in the validation or verification of the performance of a test for clinical diagnostic use that uses its RUO or IUO labelled IVD, that assistance would be considered to be evidence of a non-research or non-investigational intended use.”
The wording of the Final Guidance leaves considerable room for interpreting the marketing and sales behaviour of both vendors and clinical laboratories. These are likely to be taken up for enforcement actions by the FDA on a case-by-case basis.
As another recent commentary by law firm Hyman, Phelps & McNamara observes, the FDA “says it will take enforcement action based on the totality of the circumstances.  What that actually means remains to be seen.  As with most things with FDA, we will simply have to wait and see.”