RGA’s Global Medical Newsletter
Volume 40, January 2017

IN THIS ISSUE
2

Alzheimer’s: An Update on an Old Disease
By Lisa Duckett, M.D.

7

RGA Medical Team Update

8

Seasonality of Mortality
By Kyle Nobbe, FSA

14

Brief Report: Update on Thyroid Nodule
Imaging Guidelines
By Sharylee Barnes, M.D.

17

Longer Life Foundation: Latest News2016 Articles

Neil Wilkinson

Daniel Zimmerman

Philip Smalley

18

ReCiteRelevant insurance medicine articles

Vice President, Medical Services
nwilkinson@rgare.com

Vice President, Medical Director
dzimmerman@rgare.com

Senior Vice President
Global Chief Medical Officer
psmalley@rgare.com

19

Recent Webcast
Stephen T. Oh, M.D., Ph.D., discusses latest
developments in polycythemia vera

FROM THE EDITORS
Another year has passed and we welcome you to theJanuary 2017 edition of ReFlections – RGA’s global medical
newsletter. It has truly been our pleasure to see so many ofyou recently at various conferences and client events.
With this edition of ReFlections we introduce two new
authors as well as a new feature – the Brief Report – inwhich the author prepares a short article on a focused topic.
Dr. Lisa Duckett, Vice President and Medical Director,
provides a detailed update on Alzheimer’s disease and mild
cognitive impairment with a focus on early diagnosis anduse of biomarkers, as well as discussing new treatment
strategies.
Kyle Nobbe, Assistant Actuary, Global Research andDevelopment, introduces us to his original research into
the observations and correlations of seasonal mortality
variations. His conclusions are insightful and practical for
all insurers.

Dr. Sharylee Barnes, Vice President and Medical Director,
inaugurates our Brief Report feature with an excellent
summary of recent updates from various endocrine societieson the interpretation of thyroid sonogram imaging results.
Given the frequency of these reports in attending physician
statements, this is essential reading.
ReCite continues to bring our readers recent and relevanthighlights from the medical literature, and the Longer LifeFoundation report heralds two substantial milestones
achieved over the past year – the foundation’s 100th peerreviewed article and 100th grant.
We hope you enjoy this edition of ReFlections and wish allof our readers well in the New Year.
Thank you,
Phil, Dan, and Neilwww.rgare.com

ALZHEIMER’S: AN UPDATE ON AN OLD DISEASE
Abstract
Alzheimer’s disease (AD) was first described more than 100 years ago.
It was and still is characterized by the presence of amyloid plaques andneurofibrillary tangles (NFTs). These pathologic and histologic changes
continue to define the disease and are the focus for current research. The
brain changes can be correlated with biomarkers, imaging, and cognitive
testing. Mild cognitive impairment (MCI) may represent an important step
toward the development of dementia but may also represent a nonpathologic
state. The long prodromal period before clinically detectable declines incognition offer opportunities for intervention on multiple levels. The goal of
future therapies is to decrease the accumulation of toxic proteins in the brain
and prevent decline in cognitive function.
Given the pace at which the world’s population is aging, this complex
and heterogeneous disease may well be the next worldwide epidemic.
Alzheimer’s disease and MCI present serious challenges to the insurance
industry. Knowledge of progression factors creates opportunities for risk
stratification. A full understanding of potential future epidemiologic andtreatment trends should form the basis for insurer actuarial modeling andproduct development planning.

ABOUT THE AUTHOR

Lisa Duckett, M.D.
lduckett@rgare.com
Lisa Duckett, M.D. is Vice President andMedical Director of RGA Reinsurance
Company. She provides medical
underwriting and claims services for clients.

Introduction
Although Alzheimer’s disease (AD) was first described more than acentury ago, its complexity and heterogeneity have made early diagnosis
and treatment elusive, and its pathogenesis remains uncertain. Researchbased understanding of the disease, specifically the interplay between
beta-amyloid, phosphorylated tau, and small vessel disease of the brain,biomarkers and imaging techniques that aid in diagnosis of dementia, and
MCI definition and risk factors for disease will all be discussed. In addition,
potential areas for disease modification through medications will be covered.
Aging Population Worldwide Translates
Into Potential Dementia Epidemic
AD is the most common form of dementia, and epidemiologists predict itwill be “the” epidemic of the 21st century. For asymptomatic individuals, thelifetime risk of developing AD at age 65 is 10.5%1. The world’s population
is expanding in such a way that the highest risk cohort for developing thedisease is also going to be the fastest-growing segment of the world's
population over the next 30 years. By 2050, the U.S. Census Bureau ispredicting there will be 88 million Americans over age 65. The world’s over65 population is projected to swell to 1.6 billion by then, as well. Additionally,
Asian and South American countries will all experience a quadrupling ofindividuals over 80 years of age2.

2 |January 2017 ReFlections

AD’s Long Preclinical Course
Alois Alzheimer, M.D., described the clinical symptoms and histologic changes in the brainof a woman with presenile dementia in 1906. The histologic features Dr. Alzheimer identified
in the autopsy – amyloid plaques and neurofibrillary tangles – remain the defining features ofthe disease and the focus of AD research3.
The specific protein responsible for the formation of amyloid plaques was identified 30 years
ago4 and is the product of the cleavage of the amyloid precursor protein (APP), which istethered to the cell membrane for reasons still not clear. Once APP is cleaved
into discrete fragments by secretases, the beta amyloid protein is cut at bothends of the molecule and is released to the space outside the neuron. It thenEpidemiologists
begins to aggregate with other beta-amyloid fragments, forming oligomers,
which are believed to be the core components of the amyloid plaques. Overpredict Alzheimer'stime, other proteins are added to the misfolded oligomers and conglomerate
to form insoluble plaques4. Accumulation of amyloid plaques may precede
will be "the" epidemic
clinical symptoms by 20 years5.

of the 21st century.
The second histologic feature, the neurofibrillary tangle, is composed of
tau protein and is a component of the microtubular system in neurons. The
function of tau protein is to provide structural stability for axons and transport
nutrients and neurotransmitter-containing vesicles, from the neuronal cellbody to the axon4. The disruption of this microtubular system begins a destructive processthat is characterized by accumulation of hyper-phosphorylated tau and the aggregation of
tau fibrils, which eventually forms tangles within the cell that lead to synaptic dysfunction.
Synaptic dysfunction and loss are the findings most closely associated with cognitive decline
in brains of those with dementia6, 7. This stage of the disease is characterized by progressive
cognitive decline that correlates with a clinical diagnosis of MCI transitioning to dementia7.
Diagnosis of MCI
In 2011, the National Institute on Aging and the Alzheimer’s Association convened a working groupto revise diagnostic criteria for MCI due to AD. The working group examined clinical, cognitive, andfunctional criteria to improve the accuracy of the diagnosis and project the risk of future AD. Using
MCI clinical criteria along with cognitive screening tools, biomarkers, and imaging studies made iteasier to identify the points of transition from AD’s asymptomatic to symptomatic phase.
Early recognition of the pre-dementia state is relevant for therapeutic intervention and tobenchmark disease progression8. MCI is characterized by a change in cognition noted by
the patient or other reliable source and is diagnosed by a measureable decline from priorfunction in one or more cognitive domains. The most important of these is memory loss, asloss of episodic memory correlates with risk for progression to AD8.
Cognitive assessment is vital to the diagnosis of MCI. Tests that detect deficits in theability to acquire new information as well as retention are able to detect decrement in
episodic memory include: word list learning test, Logical Memory I and II, the Wechsler
Memory Scale, and the Visual Reproduction subsets of the Wechsler Memory Scale I and
II. Additional assessment of all cognitive domains is important, since not all MCI patients
have decrements in episodic memory8. MCI patients will typically score 1 to 1.5 standard
deviations below their age- and education-matched peers8. To fulfill the diagnosis of MCI,
other causes for the cognitive impairment must also be sought, which can include vascular,
traumatic, and toxic causes. These causes must be evaluated with the goal of determining
the likelihood of neurodegenerative disease with characteristics consistent with AD.

ReFlections January 2017| 3

Assessing the Risk for Progressionof MCI Via Biomarkers
Dementia may have a very long prodromal stage withnormal cognition. Researchers hypothesize that amyloid isdeposited in the brain during AD’s asymptomatic period5.
Detecting this process early in the prodromal period may be
an opportunity for future therapeutic intervention as well as
differentiating risks for insurance products.
As MCI develops, pathologic changes in the brain arecharacterized by the deposits of tau protein, concomitantloss of synaptic function, and degenerating neurons with
abundant NFTs5. Over time, the loss of neuronal integrity
leads to progressive cognitive decline.
Key findings indicating AD’s progression include:
predominance of amnestic or episodic
memory impairment on cognitive screening
tests paired with lower overall memory
scores, abnormal imaging studies, positive
biomarkers, and testing positive for thegene variant ApoE4. Some or all of thesevariables could form the basis for a riskscoring system predicting low to highlikelihood that MCI might progress to AD.
Fluid biomarkers in current use include
cerebrospinal fluid beta-amyloid 42(CSF42), which reflects the depositionof amyloid in the brain, and CSF tau/phosphorylated tau, which reflects
neuronal injury following amyloid
deposition. Positive results on tests forboth biomarkers confers the greatest
likelihood that MCI changes are due
to AD. One but not both markers positive confers anintermediate likelihood, and low likelihood of progression to
AD would encompass discrepant and/or ambiguous results.
Negative biomarker results have a negative predictive value,
which may be useful as well8.
Imaging studies may substantiate the risk further if they areconcordant with the fluid biomarker results. Imaging studies
assess amyloid deposition in the brain and quantify the extent
of atrophy present in the brain. PET scans that use one of therecently approved amyloid binding agents – florbetapir F-18
(AMYViD), flutemetamol F-18 (Vizamyl), or florbetaben F-18
(Neuraceq) – detect brain amyloid deposition. A volumetric
MRI can quantify volume declines in the hippocampus andrelated regions, making this test a good marker for AD13.
The results of MCI brains studied demonstrate substantial

4 |volume loss in the hippocampal region: approximately 50%
reduction in volume compared to control subjects without
known MCI13.
The detection of decreased glucose uptake during FDGPET scanning is another method for detecting the presenceof significant neuronal loss. The characteristic areas of thebrain that are the most affected are the temporal and parietal
lobes. A March 2016 article reported a sensitivity of 94%
and a specificity of 73%. This test can also correctly predicta progressive course of dementia with 91% sensitivity and a
non-progressive course with 75% specificity14, 15. Combining
biomarker results with imaging scans, cognitive testing, andclinical course of symptoms may very accurately predict thepossible development of AD8.

Biomarker Limitations
Many studies have used biomarkers to predict progressionof MCI to AD. However, due to the newness of thetechnology, there are limitations to the use of biomarkers.
It is important to note that there is a lack of standardization
between labs and thresholds for significance. Controversy
exists on how to use the biomarkers and who to evaluatewith them. The tests are expensive and may be inconsistentor misleading. Comparisons for accuracy have not been
evaluated in multivariate studies. Limited studies havelooked at combinations of biomarkers and interpretationof results for multiple biomarkers – particularly if there are
discrepant findings. Furthermore, the biomarkers are notnecessarily specific for AD and can be present in otherneurodegenerative diseases8.

January 2017 ReFlections

Small Vessel Disease Substrate for Neuronal
Degeneration and Cognitive Impairment
Inadequate clearance of amyloid plaques from the brain might
be one of the reasons beta-amyloid is found in abundance inneurodegenerative diseases. Researchers are studying theassociation between vascular pathology and the developmentof cognitive decline. Atherosclerosis and amyloid angiopathy
are the leading causes of small vessel disease in the brain9.
Lacunae and white matter lesions are ischemic events thatare commonly visualized on neuroimaging; however, lesscommonly seen are hemorrhagic lesions of blood vessels
manifested by cranial microbleeds. Such microbleeds may
explain why cardiac risk factors as well as amyloid deposition
are important in the development of chronic degenerative
brain diseases9. The atherosclerotic changes that occurin blood vessels with ischemic events are associated withcardiac risk factors: hypertension, smoking, and diabetes.
The pathogenesis of hemorrhagic events that occurs in small
vessel is related to beta-amyloid accumulation in the vessel
wall, vascular dysfunction, with resultant inflammation andvessel wall weakness to produce hemorrhages9. Both vascularchanges, ischemic and hemorrhagic, appear to be related todecreased clearance of toxic amyloid protein, local ischemia,
and ultimately cognitive decline.

To test the hypothesis that there may be a relationshipbetween the number of microbleeds and cognitive
dysfunction, the Rotterdam study, a longitudinal prospective
population-based study, evaluated individuals for bothparenchymal and cognitive changes over time. The study

ReFlections January 2017concluded that a high microbleed count of >4 is associatedwith cognitive decline on serial testing and increases therisk of dementia. The authors of the study remarked that themechanisms by which microbleeds can influence cognitive
function remain speculative; however, it appears thatmicrobleeds may be a biomarker for advanced vascular andneurodegenerative damage that then leads to progressive
cognitive decline. Whether this is related to vascular disease
that causes local ischemic damage to brain tissue or
hypertensive disease that causes decreased clearance ofamyloid is uncertain9.
Genetics of AD
Presence of genetic mutations in both the amyloid precursor
protein (APP) and the presenilin 1 and 2 mutations may
develop early-onset disease at 65 years of age or younger
with a variable time course from MCI to dementia. ApoE4
allele homozygotes also are at risk for development oflate-onset dementia and the genetic phenotype has beenused to stratify risk for the development of AD when MCI ispresent10.
Therapeutic Interventions for Disease Modification
Drug development to modify the course of AD has beenslow. The last FDA-approved drug for moderate to severeAD, memantine, was released in 200311. At
present, there are no drugs approved fortreatment of MCI, and none of the approved
medications for AD offers any clear mortality
benefit.
Researchers are developing medications
aimed at modifying steps in amyloid
processing to eliminate the production anddeposition of amyloid. Phase 3 trials are in
progress to test the efficacy of inhibition ofbeta secretase (BACE), which cleaves amyloid
into the smaller molecules with potential
to become oligomers of amyloid. Anothermedication currently in clinical trials that isdesigned to reduce amyloid production issolanezumab, a monoclonal antibody. This
medication binds amyloid protein to reduce
the formation of plaques and assists with clearance ofamyloid protein. Some encouraging results in mild AD haveprompted further studies12.
Reducing tau production is another potential method for
disease modification. The AADvac1 vaccine, also currently| 5

in clinical trials, targets the abnormal tau protein that destabilizes microtubules. Another anti-tau
medication in clinical trials, Epothilone D, is designed to stabilize the microtubules in the neurons
to decrease the propensity for the formation of neurofibrillary tangles in animal models.
A novel anti-inflammatory drug, CSP-1103, acts to reduce inflammation in the brain associatedwith the deposition of amyloid protein. The anti-inflammatory activity of this drug, currently inclinical trials as well, is directed against the microglial cells in the brain.
Additional trials are under way to determine the effect of neuroprotective agents such as insulin.
Insulin activity is reduced in the brains of individuals with AD, and restoration of normal insulinlevels seems to stabilize and improve cognition in those with amnestic mild cognitive impairment(aMCI) and those with mild to moderate AD. Nasally-administered insulin is used here because
it is quickly absorbed into the central nervous system and may not affect serum glucose or
insulin levels13. Results of the trials are encouraging; however, they are in the very early stage of
research12.
Summary
Dementia is likely to increase tremendously worldwide over the next 30 years due to the globe’s
rapidly aging population. Understanding of the disease is growing, and it is apparent it has along preclinical stage before cognitive decline actually occurs.
Abnormal accumulations of amyloid and tau proteins interact to cause AD.
Research has advanced the diagnostic accuracy of MCI and identified risk
factors for disease progression.
Vascular pathology is also important in neurocognitive disease development
and substantiates the importance of vascular health in disease prevention.
Vascular risk factor modification, particularly treatment of hypertension
and smoking cessation, appears to play an important role for initiation ofneurodegenerative processes that occur in blood vessels to include ischemic
and hemorrhagic changes.

Medications havebeen slow to develop
and few are in trials todetermine efficacy.

Medications have been slow to develop and few are in trials to determine
efficacy. Some have shown progress, but the last time the FDA approved
a drug for AD was in 2003 and no drugs are currently available for MCI. Multiple areas ofintervention are plausible for reduction of amyloid and tau proteins in the brain and are being
studied, but few medications in the more immediate production pipeline are promising.
Insurers will need to remain vigilant and informed with regard to the epidemiology,
pathophysiology, and impact of potential treatment trends for neurocognitive risks. Hopefully,
with improved predictive and diagnostic testing, risk stratification and claims experience can be
refined over time.

6 |January 2017 ReFlections

References
1. Criteria for preclinical Alzheimer’s disease – June 2,2010 / Preclinical Alzheimer’s Disease Workgroup.
[cited 2016 Sept 22] http://www.alz.org/research/
diagnostic_criteria/preclinical_recommendations.pdf
2. United States Census Bureau. An Aging World: 2015,
Census Bureau Reports March 2016. Report number
CB16-54. http://www.census.gov/newsroom/pressreleases/2016/cb16-54.html

8. Albert MS, DeKosky ST, Dickson D et al. The diagnosisof mild cognitive impairment due to Alzheimer’s disease:
Recommendations from the National Institute on Agingand Alzheimer’s Association workgroup. Alzheimer’s& Dementia 7 (2011) 270-9. http://www.alz.org/
documents_custom/diagnositic_recommendations_mci_due_to_alz_proof.pdf

3. Major Milestones in Alzheimer’s and Brain Research.
Alzheimer’s Organization. Available from http://www.alz.
org/research/science/major_milestones_in_alzheimers.
asp

9. Akoudad S, Wolters F
FJ, Viswanathan A et al.
Association of Cerebral Microbleeds With Cognitive
Decline and Dementia. JAMA Neurol.[Internet] 2016
Aug 1:73(8): 934-43. https://www.ncbi.nlm.nih.gov/
pubmed/27271785

4. The Hallmarks of AD. National Institute of Aging. [cited
2016 Sept 17]. Available from http://www.nia.nih.gov/
alzheimers/publication/part-2-what-happens-brain-ad/
hallmarks-ad

10. Bertram L, Lill CM, T
Tanzi RE. The Genetics ofAlzheimer Disease: Back to the Future. Neuron 2010
Oct 21;68(2):270–81. https://www.ncbi.nlm.nih.gov/
pubmed/20955934

5. Jack CR Jr, Knopman DS, Jagust WJ et al.
Hypothetical model of dynamic biomarkers of the
Alzheimer’s pathological cascade. Lancet Neurol.
2010 Jan; 9(1):119-28. https://www.ncbi.nlm.nih.gov/
pubmed/20083042

11. Memantine: Drug information. MedlinePlus. https://
medlineplus.gov/druginfo/meds/a604006.html

6. Bennett DA, Schneider JA, Wilson RS et al.
Neurofibrillary tangles mediate the association ofamyloid load with clinical Alzheimer disease and levelof cognitive function. Arch Neurol. 2004; 61: 378-384.
https://www.ncbi.nlm.nih.gov/pubmed/15023815

13. Therapeutics – Nasal Insulin. Alzforum. http://www.
alzforum.org/therapeutics/nasal-insulin

7.

Gomez-Isla T, Hollister R, W
West H, et al. Neuronal loss
correlates with but exceeds neurofibrillary tangles in
Alzheimer’s disease. Ann Neurol. 1997 Jan; 41(1):1724. https://www.ncbi.nlm.nih.gov/pubmed/9005861

12. Treatment Horizon. Alz.org Research Center. http://
www.alz.org/research/science/alzheimers_treatment_
horizon.asp

14. Salmon E, Gregoire MC, Delfiore G, et al. Combined
study of cerebral glucose metabolism and [11C]
methionine accumulation in probable Alzheimer's
disease using positron emission tomography. J Cereb
Blood Flow Metab. 1996 May, 16(3):399-408. https://www.ncbi.nlm.nih.gov/pubmed/8621744
15. Ramachandran TS. Alzheimer Disease Imaging.
Medscape. Updated March 15, 2016.[cited 2016 Oct
12]. http://emedicine.medscape.com/article/336281overview

RGA MEDICAL TEAM UPDATERGA welcomes the following doctors to our global network of medical officers:• Dr. Adela Osman, MBBCH, Chief Medical Research Officer of South Africa(General Practice), Johannesburg, South Africa• Dr. Shivani Sarwal, Executive Director, Underwriting (Insurance Medicine),
Kuala Lumpur, Malaysia• Dr. Elyssa Del Valle, Vice President and Medical Director (Internal Medicine),
St. Louis, Missouri (U.S.)

ReFlections January 2017

| 7

SEASONALITY OF MORTALITY
Abstract
The first few months of 2015 exhibited exceptionally high mortality
experience in several countries, including the U.S., Japan, and the U.K. T
Thisexperience was noted by insurance investment analysts, and research was
carried out during the first half of 2015 to further develop an understandingof the underlying causes. The new research built on the 2012 seasonality
research conducted by RGA1. The 2012 study had highlighted how a variety
of demographic, socioeconomic, and geographic factors influence thedegree and direction of seasonal mortality. The 2015 research focused on
global seasonality, and how flu and pneumonia (F&P) mortality correlateswith other causes of death. These findings were used to monitor the 2016season, which turned out to be less severe than the 2014-15 season,
when flu vaccine effectiveness was especially poor. This article focuses onunderstanding how seasonality varies by country and region, and how F&P
mortality correlates with other causes of death.
Introduction
Seasonality refers to a trend pattern that repeats every 12 months. In
insurance, knowledge of seasonality’s impact on mortality is not new. Life
insurers sometimes experience poor financial results stemming from large
fluctuations of claims in colder months. The ability to understand the main
drivers of seasonal mortality, and therefore why certain years have higher
seasonal mortality than expected, can be vital for insurer reporting andplanning.

ABOUT THE AUTHOR

Kyle Nobbe, FSA
knobbe@rgare.com
Kyle Nobbe is a Fellow of the Society ofActuaries (FSA) and an assistant actuary in
RGA’s Global Research and Development
department. He works on various research
initiatives around the globe ranging fromlife and morbidity studies to future datasolutions for the insurance industry.

Although higher mortality is expected in winter months, the magnitude ofseasonality can vary by year and is unpredictable. One method of assessing
the degree of seasonality by year is via the winter-to-summer ratio. This ratio
is defined as shown below.
Winter-to-Summer Ratio =where December deaths are from the prior year.
Note that the ratio’s values would be inverted for southern hemispherecountries (i.e., the winter months would be defined as June, July and August,and the summer months as December, January and February).
While all years demonstrate increased seasonal mortality, Figure 1 also
shows that some years have had exceptionally high seasonal mortality.

8 |January 2017 ReFlections

Source: Centers for Disease Control (U.S.), Japan Government Statistics, E&W, ONS, RGA

Global Seasonality
Geographic location is one of the most important drivers of the degree and direction ofseasonal mortality. A company’s distribution of business by location could have a significant
impact on their exposure to seasonality.
In Figure 2, monthly mortality data from the United
Nations2 was used to create a Base 100 Index. The
index’s purpose was to examine the differences inseasonal mortality among countries in the northernhemisphere, the southern hemisphere, and near theequator. (For this chart, the equatorial region was
defined as limited to countries located within latitudes
20 degrees north and south of the equator.)
Not surprisingly the southern hemisphere’s seasonality
curve mirrors that of the northern hemisphere. The
seasonality curve is less dramatic for equatorial
countries, as climate differences by season in thisregion are far less pronounced.

ReFlections January 2017

A company's
distribution of businessby location could have asignificant impact on its
exposure to seasonality.

| 9Source: United Nations, RGA

The Base 100 Index explains positive and negative variances of death counts across years
relative to a trending average. Months with an index of 110, for example, have 10% higher
mortality than the monthly average for that time period, whereas months with an index of 90
would have mortality that is 10% lower than the average trend.
An additional assessment of seasonal variation by location explores the impact of distance fromthe equator. Figure 3 compares the average Base 100 Index for the northern hemisphere’s
winter months of more than 50 of the world’s most populated countries to their mediangeographic latitude. Plotting the winter Base 100 Index against latitude yields the strong
correlation shown below. If the southern hemisphere’s winter months were used for the chart,
the same correlation would hold but with a negative sloping trend line. (Note that extreme
northern countries, defined as those with latitudes around 70 degrees, appear to experience
less seasonality relative to most countries at latitudes between 40 and 50 degrees.)

Source: United Nations, RGA

10 |January 2017 ReFlections

Flu and Pneumonia Seasonal Mortality and Other Causes of Death
Flu and pneumonia (F&P) mortality is the most winter-specific seasonal cause of death,followed by all other respiratory causes. Unnatural deaths such as suicide, accidents, andhomicides are summer seasonal; i.e., these deaths tend to trend higher in the summer. The
medical causes of death that are grouped broadly in Figure 4 are also winter seasonal,
albeit not as significant as respiratory causes, with the exception of cancer.
Figure 4 demonstrates this by charting the winter-to-summer ratios for different causes ofdeath in the U.S.

Source: Centers for Disease Control (U.S.), RGA

Figure 4 also sets the stage for identifying correlations and causations. The data suggeststhat flu and pneumonia are the most seasonal causes of mortality. Thus it would be
expected that in years with higher than normal F&P incidence, or where in the case of
influenza there was poor vaccine match with circulating strain (as was seen in the 20142015 season), exceptionally high seasonal mortality could be experienced. Additionally,F&P involves a pro-inflammatory process, and inflammation is a driver in many otherdiseases, so this may explain seasonal mortality for causes of deaths other than respiratory.
This observation is supported by Centers for Disease Control and Prevention (CDC)3
position on individuals at high risk for flu-related complications. The CDC lists asthma,
neurological conditions, lung disease, heart disease, diabetes, kidney, liver, blood, andmetabolic disorders, obesity, and weakened immune systems (e.g. HIV/AIDs and cancer) as
conditions that heighten the risk for flu complications.
The only inconsistency between our data analysis and the CDC’s opinion is the conclusion
with regard to cancer. Cancer patients, especially the terminally ill, tend not to exhibit
seasonal mortality for a number of reasons, such as: more aggressive medical treatment;
better nutrition; a strong support system; and increased sensitivity to factors that may
prolong survival, such as immunizations and avoidance of crowds in winter4.

ReFlections January 2017| 11

Figure 5 shows the correlations, or possible causal connections, between F&P mortality
and overall winter seasonality for the U.S. and Japan. Using a scatterplot graph, it plots
influenza and pneumonia deaths against all other medical deaths and compares thepercentage of excess deaths that occur each month. (The percentage of excess deaths
for a given month is defined as the additional number of deaths in a month relative to thetrending average.)
Figure 5 demonstrates the positive relationship between increasing F&P deaths in the U.S.
and increasing all other medical deaths. When fitting a linear trend line to the graph, thegoodness-of-fit (i.e., the extent to which observed data match the trend line) is about 82%,
signifying a strong correlation. The graph’s trend line also shows that all other medical
deaths increase by about 20% to 25% of the increase of F&P deaths. For example, if F&P
deaths exceed the norm by 40%, then all other medical deaths would exceed their norms
by about 16% to 20%.
Figure 5 also shows data for Japan using the same methodology. Results look very similar,
except the trend line’s goodness-of-fit is much stronger, at 91%. The trend line also implies
that all other medical excess deaths increase by about 60% of what the F&P deaths
increase. This is a much higher proportion than the U.S., and could be due either to the
population density or other demographic characteristics. Lastly, Japan’s F&P excess deaths
never exceed 35% while the U.S. exceeds 100%, which could mean that Japan’s F&P
mortality is more controlled. (England and Wales data is not shown on this graph due to thedifferences in data availability.)

Source: Centers for Disease Control (U.S.), Japan Government Statistics, RGA

Unfortunately, identifying whether F&P mortality is not just correlated with seasonalmortality, but actually causes it, is very difficult to distinguish. Given, however, howsignificant the correlation is at the different deep-dives of the analysis, some level of
causation might exist.

12 |January 2017 ReFlections

Implications for Insurers
The relationship between F&P mortality and seasonality has potential direct implications for
insurance companies. As flu season predictions continue to evolve and improve, insurancecompanies may eventually be able to better prepare for seasonal as well as potentiallyadverse experience and financial results. This greater knowledge could also result in an
enhanced understanding of how each individual company’s seasonality differs, based on
their policyholders’ exposure to the complications of infectious diseases.
It is also important to understand the relationshipbetween the seasonality of a general population andthat of insured lives. For insured lives, the latter istypically much less significant than the former for avariety of reasons, including: 1) age demographics
that skew younger for insured lives; 2) the generally
higher socioeconomic status of policyholders and their
better access to health care; 3) volatility of claim size;and 4) lags in claim reporting1.
An understanding of seasonality can also be quite
valuable when interpreting partial year claims
experience analyses. Results are often skewed byexternal stimuli such as seasonality. Underwriters or
medical directors who utilize an experience study tomake decisions need to bear such factors in mind.

An understanding of
seasonality can bequite valuable wheninterpreting partial
year claims experience
analyses.

The most interesting aspect of the implications of seasonality for insurance companies isthat there is still much to learn. Currently, forecasting and predicting F&P seasonality arestill in their infancy. When forecasts become more accurate, insurance companies will
have a new tool to monitor and analyze seasonal claims experience. Eventually there mighteven be new ways for companies to mitigate seasonal risk to their earnings. This is an areaof great interest to insurers, and will undoubtedly receive more attention and research in
the future.
References
1. Rozar, Tim and Rushing, Scott. Impact of Seasonality on Mortality. SOA, 2012
2. Monthly Bulletin of Statistics. Population and Vital Statistics Report. [Online] United
Nations Statistics Division. http://data.un.org/Data.aspx?d=POP&f=tableCode%3A65
3. CDC. People at High Risk of Developing Flu–Related Complications. Seasonal
Influenza. [Online] CDC, 2016. http://www.cdc.gov/flu/about/disease/high_risk.htm
4. ASCO University. Sesonal mortality in terminally ill cancer patients. (Online) http://
meetinglibrary.asco.org/content/32137-65

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UPDATE ON THYROID NODULEIMAGING GUIDELINESIn May 2016, The American Association of Clinical Endocrinologists (AACE),
the American College of Endocrinology (ACE), and the Associazione Medici
Endocrinologi (AME) issued the latest update of their Medical Guidelines forClinical Practice for the Diagnosis and Management of Thyroid Nodules1.

ABOUT THE AUTHOR

One of the goals of this update was to stratify the risk represented bydifferent ultrasound images of thyroid nodules. Older guidelines did not havethe same emphasis on ultrasound patterns, which underwriters are seeing
more frequently in attending physician statements2, 3, 4.
The update includes fine needle aspiration (FNA) recommendations
as well as five histologic classifications and comprehensive treatment
recommendations. The latter two will not be addressed in this brief report.
The new update also addresses both the American and British Thyroid
Associations ultrasound thyroid nodule classification schemes.
Prevalence of Thyroid Nodules
Large nodules exist in 5% to 8% of the healthy adult population6, 8 whereas
small nodules (<10 mm) exist in 50% to 60%1, 5. Only about 2.5% of all
thyroid nodules are malignant6, 7.

Sharylee Barnes, M.D.
sbarnes@rgare.com
Sharylee Barnes, M.D., is Vice President
and Medical Director for RGA Reinsurance
Company. She provides case consultation
as well as medical support and education forclients worldwide.

Patient Characteristics
The presence of any historical or clinical findings can impact theinterpretation of the guidelines from the AACE/ACE/AME. Adverse history
can include personal or family history of thyroid cancer, multiple endocrine
neoplasia (MEN), or personal history of neck irradiation. Clinical findingssuch as dysphonia, dysphagia, dyspnea, anterior neck pain, nodule enlarging
on exam, lymphadenopathy, and presence of hypo- or hyperthyroidism add
additional risk consideration6, 8. Age under 14 years or over 70 also increases
malignancy potential, as does being male1.
Guidelines: Malignancy Risk and Recommended FNA Based on
Ultrasound Findings1, 6, 7, 4, 9
Thyroid ultrasound results can be divided into favorable and unfavorable
features. As the number of unfavorable features increases, so does the riskof malignancy1, 6, 9, 10.
These guidelines are for individuals without adverse histories and clinicalfeatures described above in “Patient Characteristics” unless otherwise noted.
Any nodule <5 mm should be monitored and should not be biopsied with
FNA regardless of the ultrasound characteristics. Even with the adversefeatures FNA is not recommended if scintigraphy shows normal function.
Patients with multinodular goiter have the same risk stratification guidelines
for their nodules as would a patient with a solitary nodule1. For multinodular
goiter, each nodule is classified and the nodules with the most adversefeatures should be biopsied. The guidelines support performing FNA on no
more than two nodules1.

14 |January 2017 ReFlections

Class 1 Lesion: Low-Risk Malignancy - ~1%• cysts with fluid component >80%
• isoechoic spongiform nodules, either confluent or withregular halo
• FNA if >20 mm and with adverse patient history
features present (described on previous page) or
enlarging nodule
Class 2 Lesion: Intermediate Risk Malignancy - ~ 5% to 15%• not a definite benign appearance• cystic and some solid components• slightly hypoechoic, isoechoic, or indeterminate
hyperechoic spots• ovoid to round shape• margins may be smooth or ill-defined• intranodular vascularization• continuous calcified rim• elevated stiffness at elastography• FNA if >20 mm
Class 3 Lesion: High-Risk Malignancy - ~50% to 90%
Has at least one of the following suspicious features:Managing Ultrasound Results
The principal goal of a thyroid ultrasound is to find orrule out cancer1, 8, 5. If a nodule is found, appropriate
clinical follow-up must acknowledge the dangers of overinvestigation1, 11, 12, which can include excess radiation,
bleeding, surgical complications, anxiety, anesthesia
risk, hospital-acquired infections, and scarring. Surgicalcomplications can include vocal cord paralysis (due to nerve
damage), hypothyroidism and hypoparathyroidism7, 11, 12.
Underwriting Considerations
Understanding the natural history of lesions found during
thyroid imaging and whether or not they are meaningful toprognosis or represent increased mortality or morbidity risk
is essential to underwriting.
Thyroid ultrasound reports are frequently encounteredin attending physician statements. It is essential for risk
assessors to understand the risk associated with findings
even if not clearly stated in the report, and from there
determine if appropriate follow-up testing has beenscheduled or performed. The historical and clinical featuresof the proposed insured must also be considered in order
to interpret ultrasound findings properly. Taking all of thisinformation into consideration should assist in reaching anappropriate underwriting decision.

• markedly hypoechoic• spiculated or microlobulated
margins• microcalcifications• height greater than width• disruption of a calcified rim• capsular abutment• pathologic lymphadenopathy• FNA if:
– Nodule >10 mm– extension beyond thethyroid– pathologic lymph nodes– vascular features or mass effect on the jugular veinby the lymph nodes– consider FNA if nodule is 5 mm to 10 mm,
depending on clinical setting

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| 15

References
1. The American Association of Clinical Endocrinologists(AACE), the American College of Endocrinology(ACE), and the Associazione Medici Endocrinologi(AME) Medical Guidelines for Clinical Practice for the
Diagnosis and Management of Thyroid Nodules – 2016
Update. Endocrine Practice Vol 22 (Suppl 1) May 2016.
https://www.aace.com/publications/guidelines
2. Yoon JH, Shin HJ, Kim EK, Moon HJ, Roh YH, Kwak
JY. Quantitative Evaluation of Vascularity Using 2-D
Power Doppler Ultrasonography May Not Identify
Malignancy of the Thyroid. Ultrasound Med Biol. 2015
Nov;41(11):2873-83. https://www.ncbi.nlm.nih.gov/
pubmed/26298035
3. Moon HJ, Kwak JY
JY, Kim MJ, Son EJ, Kim EK. Can
Vascularity at Power Doppler US Help Predict Thyroid
Malignancy? Radiology. 2010 Apr,255(1):260-9.
https://www.ncbi.nlm.nih.gov/pubmed/20308462
4. Kwak JY
JY, Jung I, Baek JH. Korean Society of Thyroid
Radiology (KSThR); Korean Society of Radiology et
al. Image Reporting and Characterization System for
Ultrasound Features of Thyroid Nodules: Multicentric
Korean Retrospective Study. Korean J Radiol. 2013 JanFeb; 14(1):110-7. https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC3542293/
5. Gharib H, Papini E, Paschke R, Duick DS, Valcavi
R, Hegedüs L, Vitti P; AACE/AME/ETA Task
Force on Thyroid Nodules. American Associationof Clinical Endocrinologists, Associazione Medici
Endocrinologi, and European Thyroid Association
medical guidelines for clinical practice for the diagnosis
and management of thyroid nodules: executive
summary of recommendations. J Endocrinol Invest.
2010;33(5 Suppl):51-6. https://www.ncbi.nlm.nih.gov/
pubmed/20543551
6. Yeung MJ, Serpell JW. Management of the solitary
thyroid nodule. Oncologist. 2008 Feb;13(2):105-12.
https://www.ncbi.nlm.nih.gov/ubmed?term=The+Onco
logist%5BJour%5D+AND+2008%5Bpdat%5D+AND+Yeung+M%5Bauthor%5D+AND+solitary&TransSche
ma=title&cmd=detailssearch

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7.

Haugen BR, Alexander EK, Bible KC et al. 2015
American Thyroid Association Management
Guidelines for Adult Patients with Thyroid Nodules
and Differentiated Thyroid Cancer: The American
Thyroid Association Guidelines Task Force on Thyroid
Nodules and Differentiated Thyroid Cancer. Thyroid.
2016 Jan;26(1):1-133. https://www.ncbi.nlm.nih.gov/
pubmed/26462967

8. Perros P
P, Boelaert K, Colley S, British Thyroid
Association et al. Guidelines for the Management ofThyroid Cancer. Clin Endocrinol (Oxf). 2014 Jul;81
Suppl 1:1-122. https://www.ncbi.nlm.nih.gov/pubmed?t
erm=%22Clinical+endocrinology%22%5BJour%5D+A
ND+81%5Bvolume%5D+AND+2014%5Bpdat%5D+
AND+management+guidelines&TransSchema=title&cm
d=detailssearch
9. Campanella P, Ianni F
F, Rota CA, Corsello SM,
Pontecorvi A. Quantification of cancer risk of eachclinical and ultrasonographic suspicious feature of
thyroid nodules: a systematic review and meta-analysis.
Eur J Endocrinol. 2014 Apr 10;170(5):R203-11. https://www.ncbi.nlm.nih.gov/pubmed/?term=Campanella+P+
quantification+2014
10. Laulund AS, Nybo M, Brix TH, Abrahamsen B,
Jørgensen HL, Hegedüs L. Duration of thyroid
dysfunction correlates with all-cause mortality. The
OPENTHYRO Register Cohort. PLoS One. 2014
Oct 23;9(10):e110437. https://www.ncbi.nlm.nih.gov/
pubmed/?term=laulund+AS+all-cause+2014
11. Abu-Y
Abu-Yousef MM, Larson JH, Kuehn DM, Wu AS, Laroia
AT. Safety of ultrasound-guided fine needle aspiration
biopsy of neck lesions in patients taking antithrombotic/
anticoagulant medications. Ultrasound Q. 2011
Sep;27(3):157-9. https://www.ncbi.nlm.nih.gov/
pubmed/21873852
12. van Roosmalen J, van Hemel B, Suurmeijer A, Groen H,
Ruitenbeek T, Links TP
TP, Plukker JT. Diagnostic value andcost considerations of routine fine-needle aspirations in
the follow-up of thyroid nodules with benign readings
Thyroid. 2010 Dec;20(12):1359-65. https://www.ncbi.
nlm.nih.gov/pubmed/20954810

January 2017 ReFlections

The Longer Life Foundation partnership
between RGA and Washington
University in St. Louis is approachingits 20th anniversary of granting seedmoney to researchers investigating theenhancement of disease prognostication
accuracy and the improvement of quantityand quality of life.
Over the years, LLF has provided several
benefits to the global life insurance
industry. These include access to
Washington University's world-classacademics engaged in cutting-edge
research on human health and topical
webcasts by top insurance industry chief
medical officers to sponsorship of eventsand lectures on topics of immediate andlong-term interest such as aging, obesity,
cancer, cardiovascular disease, infection
risk, longevity, and comorbidity. The
results of this research ultimately filter
to the insurance industry, strengthening
product development
Since late 2015, LLF has achieved
several important milestones: thepublication of the 100th peer-reviewed
article generated from LLF-funded
research, the disbursement of the100th research grant, and the complete
redesign of our www.longerlife.org
website, supported by a dedicatedTwitter feed. With peer-reviewed articles
now numbering 106, LLF is increasingly
being recognized as both recognizing
and supporting research that produces
medical advances benefiting humanhealth.

ReFlections January 20172016 ARTICLES
1. High-Protein Intak
Intake During Weight Loss Therapy Eliminates theWeight Loss-Induced Improvement in Insulin Action in Obese
Menopausal Women
Smith GI, Yoshino J, Kelly SC, Reeds DN, Okunade A, Patterson BW,
Klein S (LLF grantee), Mittendorfer B. (LLF grantee)
Cell Reports, Oct. 11, 2016
http://www.cell.com/cell-reports/abstract/S2211-1247(16)31286-4?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%
2FS2211124716312864%3Fshowall%3Dtrue
2. Predicting All-Cause Mortality From Basic Physiology in the
Framingham Heart Study
Zhang WB, Pincus Z (LLF grantee)
Aging Cell, Feb. 15, 2016
https://www.ncbi.nlm.nih.gov/pubmed/26446764
3. Effects of Moderate and Subsequent Progressive W
Weight Losson Metabolic Function and Adipose Tissue Biology in Humans
with Obesity
Magkos F, Fraterrigo G, Yoshino J, Luecking C, Kirbach K, Kelly SC, de
Las Fuentes L, He S, Okunade AL, Patterson BW, Klein S (LLF grantee)
Cell Metabolism, Feb. 22, 2016
https://www.ncbi.nlm.nih.gov/pubmed/26916363
4. Probiotic Gut Bacteria Enhance Cancer Immunotheraphy in a
Mouse Model of Melanoma
Dey N, Ciorba MA (LLF grantee)
Gastroenterology, May 26, 2016
https://www.ncbi.nlm.nih.gov/pubmed/27238844
5. Long-Term
Long-T
Administration of Nicotinamide Mononucleotide
Mitigates Age-Associated Physiological Decline in Mice
Mills KF, Yoshida KF, Stein LR, Grozio A, Shunsuke K, Sasaki Y, Redpath
P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI (LLF grantee)
Cell Metabolism, October 27, 2016
Visit us online at www.longerlife.org or follow us on Twitter @LongerLifeOrg| 17

ReCiteInteresting and relevant articles to the field of insurance medicine recently
appearing in the literature...

Intensive vs. Standard Blood Pressure Control and Cardiovascular Disease
Outcomes in Adults Aged >75 Years: A Randomized Clinical Trial
Williamson J, et al. JAMA 2016 Jun 28;315(24):2673-82. Doi:10.1001/jama.2016.7050
https://www.ncbi.nlm.nih.gov/pubmed/27195814
This study was designed to evaluate the impact of intensive (<120 mm Hg) compared withstandard (<140 mmHg) systolic blood pressure treatment targets in persons aged 75 years andolder with hypertension without diabetes. Among the 2,636 participants who were followed
for a mean period of 3.14 years there was a significantly lower (HR 0.66) risk of cardiovascular
events and lower all-cause mortality (HR 0.67) in the intensive treatment group compared withthe standard treatment group. Serious adverse events were comparable in both groups. Whilefew insurance applicants are currently greater than 75 years of age, that number may increasein the coming years. From an older-age underwriting point of view, the results of this study
demonstrate better outcomes in those with more aggressive blood pressure control.
Atrial Fibrillation and Risks of Cardiovascular Disease, Renal Disease, and Death:
Systematic Review and Meta-analysis
Odutayo A, et al. BMJ 2016;354:i4482. Doi: 10.1136/bmj.i4482
http://www.bmj.com/content/354/bmj.i4482
The authors performed a meta-analysis of 109 eligible studies incorporating more than 9.5
million subjects. The authors were able to confirm that atrial fibrillation (AF) was associatedwith increased overall all-cause mortality (RR 1.46) and stroke (RR 2.42). However, the risk did
not stop there. They also demonstrated increase relative risk for cardiovascular (CV) mortality(RR 2.03), CV events (RR 1.96), ischemic heart disease (RR 1.61), sudden cardiac death (RR1.88), heart failure (RR 4.99), chronic kidney disease (RR 1.64), and peripheral arterial disease(RR 1.31). Given that the risks of some of these are near or greater than the risk of stroke theauthors concluded that greater efforts are needed to reduce the risk of non-stroke CV outcomesin adults with AF. Insurers should consider all of these complications in detail especially whendeveloping living benefits products which might be offered to individuals with a history of AF.
70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer
Cardoso F, et al. N Engl J Med 2016 Aug 25;375:717-29. doi: 10.1056/NEJMoa1602253
http://www.nejm.org/doi/full/10.1056/NEJMoa1602253
This was a randomized Phase 3 study of women with early stage breast cancer deemed to beat high clinical risk and low genomic risk and vice versa, based upon MammaPrint, the 70-genesignature genomic test. The groups were divided into chemotherapy recipients and those who
did not receive chemotherapy. Those with high clinical risk and low genomic risk who did notreceive chemotherapy only had a 1.5% lower five-year survival rate without distant metastasis
compared with those receiving chemotherapy. Those with low clinical and high genomic risk
had no statistically significant outcome difference regardless of whether or not chemotherapy
was used. If a 1.5% lower survival rate is acceptable, the authors conclude that for womenwith high risk clinical disease and low risk MammaPrint results, a 46.2% reduction in the useof chemotherapy in that group could be realized. From an insurance point of view, there would
likely be little difference in mortality outcomes, yet potentially significantly less morbidity andhealth care costs if chemotherapy is not utilized.

18 |January 2017 ReFlections

Association Between Helicobacter pylori Eradication and Gastric Cancer Incidence: A
Systematic Review and Meta-analysis
Lee YC, et al. Gastroenterology 2016 May;150:1113-24.doi: 10.1053/j.gastro.2016.01.028.
https://www.ncbi.nlm.nih.gov/pubmed/26836587
A systematic review and meta-analysis were performed to investigate the effects of Heliobacter
pylori (H pylori) eradication on the incidence of gastric cancer
cancer. Twenty-four studies were selected,
incorporating 48,064 individuals and 340,255 person-years of follow up. After adjusting forbaseline cancer incidence, those receiving H pylori eradication therapy had a pooled incidence
rate ratio of gastric cancer of 0.53 compared with those not receiving this therapy
therapy. The authors
also reported their data demonstrated that eliminating H pylori when atrophic gastritis andintestinal metaplasia had already developed still contributed to a reduction in the gastric cancer
incidence. Underwriting H pylori and gastric cancer risk does vary somewhat geographicallyglobally. Nonetheless, this paper would suggest that potentially more favorable underwriting action
can be taken when it is known or documented that H pylori has been eradicated.

RECENT WEBCAST
Latest Developments in Polycythemia Vera
Presenter: Stephen T. Oh, M.D. Ph.D.
Assistant Professor, Medicine, Division of Hematology, Washington
University School of Medicine in St. Louis
Polycythemia vera (PV) is a chronic stem cell disorder that can cause
severe complications and premature death. Dr. Oh, whose research
into phenotypes of PV is currently being funded by The Longer LifeFoundation, discusses the current state of knowledge of PV.
To arrange to view this webcast and others, please contact jchurchill@rgare.com.

ReFlections January 2017| 19

© 2017, Reinsurance Group of America, Incorporated. All rights reserved. No part of this publication may be reproduced in any form without the prior permission of the publisher. For requests to reproduce in part or entirely, please contact: publications@rgare.com. RGA has made all reasonable efforts to ensurethat the information provided in this publication is accurate at the time of inclusion and accepts no liability for any inaccuracies or omissions. None of theinformation or opinions contained in this publication should be construed as constituting medical advice.